Prolyl hydroxylase inhibitors and methods of use

ABSTRACT

The present disclosure relates to HIF- 1 α prolyl hydroxylase inhibitors, compositions which comprise the HIF- 1 α prolyl hydroxylase inhibitors described herein and to methods for controlling, inter alia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, and anemia.

PRIORITY

This application is a Continuation application Ser. No. 14/854,080,filed Sep. 15, 2015, now U.S. Pat. No. 9,598,370, which is aContinuation Application of U.S. application Ser. No. 14/568,200, filedon Dec. 12, 2014, which is a Continuation Application of U.S.application Ser. No. 14/062,011, filed Oct. 24, 2013, now U.S. Pat. No.8,940,773, which is a Divisional Application of U.S. application Ser.No. 13/681,876, filed on Nov. 20, 2012, now U.S. Pat. No. 8,598,210,which is a Continuation of U.S. application Ser. No. 12/860,073, filedon Aug. 20, 2010, now U.S. Pat. No. 8,343,952, which is a ContinuationApplication of U.S. application Ser. No. 11/821,936, filed Jun. 26,2007, now U.S. Pat. No. 7,811,595, which claims the benefit ofProvisional Application Ser. No. 60/816,522 filed on Jun. 26, 2006, theentire disclosures of which are incorporated herein by reference intheir entirety.

FIELD OF THE DISCLOSURE

The present disclosure relates, in some aspects, to HIF-1 α prolylhydroxylase inhibitor compounds and pharmaceutically acceptable saltsthereof, compositions comprising the HIF-1 α prolyl hydroxylaseinhibitor compounds, and to methods for treating or controlling, interalia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD),heart failure, ischemia, and anemia.

BACKGROUND OF THE DISCLOSURE

HIF-1 α under normal healthy conditions wherein the cells have asufficient supply of oxygen is readily converted to a degraded form byone of several prolyl hydroxylase enzymes, inter alia, EGLIN. When cellsundergo hypoxia, this enzymatic transformation is slow or entirelystopped and HIF-1 α begins to build up in the cell. When this build upof HIF-1 α occurs, this protein combines with another factor, HIF-1 βwhich together form an active transcription factor complex. Thistranscription factor then activates several biological pathways whichare present as a response to and a means for alleviating the body'sstate of hypoxia. These responses include, inter alia, angiogenic,erythropoietic (EPO), glucose metabolism, and matrix alterationresponses.

In patients where there is a need for stimulating one or more of theseresponses, for example, in patients in need of increased tissue oxygendue to peripheral vascular disease (PVD), inhibiting the EGLIN enzymewill stimulate the body's own angiogenic response without theconsequences of oxygen deficiency. In addition, in diseases of ischemia,inter alia, CAD and anemia, stimulation of angiogenic, erythropoietic,and metabolic adaptation would be expected to provide therapeuticbenefits.

Therefore there continues to be a long felt need for compounds thatinhibit prolyl hydroxylase enzymes and thereby regulate theconcentration of HIF-1α in cells so as to induce angiogenic orerythropoietic responses and therefore treat diseases related to hypoxiaor anemia.

SUMMARY OF THE DISCLOSURE

The substituted aryl or heteroaryl amide compounds of the presentdisclosure are a new class of compounds that can inhibit HIF-1α prolylhydroxylase, thus resulting in improvement in blood flow, oxygendelivery and energy utilization in ischemic tissues, or upregulate theproduction of erythropoietin so as to treat anemia.

Disclosed herein are compounds and pharmaceutically acceptable saltsthereof, and/or pharmaceutical compositions thereof comprising:

-   -   a) an effective amount of one or more compounds according to the        present disclosure; and    -   b) an excipient.

The present disclosures also relate to methods for controlling, interalia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD),heart failure, ischemia, and/or anemia.

The present disclosures also relate to methods for regulating bloodflow, oxygen delivery and/or energy utilization in ischemic tissues,wherein the methods can comprise administering to a human an effectiveamount of one or more compounds or pharmaceutically acceptable saltsdisclosed herein.

These and other objects, features, and advantages will become apparentto those of ordinary skill in the art from a reading of the followingdetailed description and the appended claims. All documents cited hereinare in relevant part, incorporated herein by reference; the citation ofany document is not to be construed as an admission that it is prior artwith respect to the present disclosure.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 Immunoblot analysis of nuclear extracts demonstratingstabilization of HIF-1α in mouse liver by{[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid

FIG. 2 . An example of how the erythropoietin level is elevated versusvehicle in mouse serum after oral dosing of{[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}-acetic acid.

DETAILED DESCRIPTION OF THE DISCLOSURE

In this specification and in the claims that follow, reference will bemade to a number of terms, which shall be defined to have the followingmeanings:

By “pharmaceutically acceptable” is meant a material that is notbiologically or otherwise undesirable, i.e., the material can beadministered to an individual along with the relevant active compoundwithout causing clinically unacceptable biological effects orinteracting in a deleterious manner with any of the other components ofthe pharmaceutical composition in which it is contained.

Throughout the description and claims of this specification the word“comprise” and other forms of the word, such as “comprising” and“comprises,” means including but not limited to, and is not intended toexclude, for example, other additives, components, integers, or steps.

As used in the description and the appended claims, the singular forms“a,” “an,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a composition”includes mixtures of two or more such compositions.

“Optional” or “optionally” means that the subsequently described eventor circumstance can or cannot occur, and that the description includesinstances where the event or circumstance occurs and instances where itdoes not.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. It is also understood that there are a number of valuesdisclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that when a value is disclosed, then“less than or equal to” the value, “greater than or equal to the value,”and possible ranges between values are also disclosed, as appropriatelyunderstood by the skilled artisan. For example, if the value “10” isdisclosed, then “less than or equal to 10” as well as “greater than orequal to 10” is also disclosed. It is also understood that throughoutthe application data are provided in a number of different formats andthat this data represent endpoints and starting points and ranges forany combination of the data points. For example, if a particular datapoint “10” and a particular data point “15” are disclosed, it isunderstood that greater than, greater than or equal to, less than, lessthan or equal to, and equal to 10 and 15 are considered disclosed aswell as between 10 and 15. It is also understood that each unit betweentwo particular units are also disclosed. For example, if 10 and 15 aredisclosed, then 11, 12, 13, and 14 are also disclosed.

The term “organic unit” as described herein refers to groups or moietiesthat comprise one or more carbon atoms and which form a portion of oneof the compounds or pharmacetucally acceptable salts thereof. Forexample, many of the substitutent units referred to elsewhere herein areorganic units. In order to effectively function in the context of theirpresence in the compounds and/or salts disclosed herein, the organicunits should often have variable ranges of restricted size and/ormolecular weight, so as to provide desired binding to the targetenzymes, solublility, bioabsorption characteristics. For example,organic unit can have, for example, 1-26 carbon atoms, 1-18 carbonatoms, 1-12 carbon atoms, 1-8 carbon atoms, or 1-4 carbon atoms. Organicunits often have hydrogen bound to at least some of the carbon atoms ofthe organic units, and can optionally contain the common heteroatomsfound in substituted organic compounds, such as oxygen, nitrogen,sulfur, and the like, or inorganic atoms such as halogens, phosphorus,and the like. One example, of an organic radical that comprises noinorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In someembodiments, an organic radical can contain 1-10 inorganic heteroatomsbound thereto or therein, including halogens, oxygen, sulfur, nitrogen,phosphorus, and the like. Examples of organic radicals include but arenot limited to an alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, mono-substituted amino, di-substituted amino, acyloxy,cyano, carboxy, carboalkoxy, alkylcarboxamido, substitutedalkylcarboxamido, dialkylcarboxamido, substituted dialkylcarboxamido,alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy,substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl,heteroaryl, heterocyclic, or substituted heterocyclic radicals, whereinthe terms are defined elsewhere herein. A few non-limiting examples oforganic radicals that include heteroatoms include alkoxy radicals,trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals andthe like.

Substituted and unsubstituted linear, branched, or cyclic alkyl unitsinclude the following non-limiting examples: methyl (C₁), ethyl (C₂),n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃), n-butyl (C₄),sec-butyl (C₄), iso-butyl (C₄), tert-butyl (C₄), cyclobutyl (C₄),cyclopentyl (C₅), cyclohexyl (C₆), and the like; whereas substitutedlinear, branched, or cyclic alkyl, non-limiting examples of whichincludes, hydroxymethyl (C₁), chloromethyl (C₁), trifluoromethyl (C₁),aminomethyl (C₁), 1-chloroethyl (C₂), 2-hydroxyethyl (C₂),1,2-difluoroethyl (C₂), 2,2,2-trifluoroethyl (C₃), 3-carboxypropyl (C₃),2,3-dihydroxycyclobutyl (C₄), and the like.

Substituted and unsubstituted linear, branched, or cyclic alkenylinclude, ethenyl (C₂), 3-propenyl (C₃), 1-propenyl (also2-methylethenyl) (C₃), isopropenyl (also 2-methylethen-2-yl) (C₃),buten-4-yl (C₄), and the like; substituted linear or branched alkenyl,non-limiting examples of which include, 2-chloroethenyl (also2-chlorovinyl) (C₂), 4-hydroxybuten-1-yl (C₄),7-hydroxy-7-methyloct-4-en-2-yl (C₉),7-hydroxy-7-methyloct-3,5-dien-2-yl (C₉), and the like.

Substituted and unsubstituted linear or branched alkynyl include,ethynyl (C₂), prop-2-ynyl (also propargyl) (C₃), propyn-1-yl (C₃), and2-methyl-hex-4-yn-1-yl (C₇); substituted linear or branched alkynyl,non-limiting examples of which include, 5-hydroxy-5-methylhex-3-ynyl(C₇), 6-hydroxy-6-methylhept-3-yn-2-yl (C₈),5-hydroxy-5-ethylhept-3-ynyl (C₉), and the like.

Substituted and unsubstituted “alkoxy” are used herein denotes a unithaving the general formula —OR¹⁰° wherein R¹⁰⁰ is an alkyl, alkylenyl,or alkynyl unit as defined herein above, for example, methoxy,methoxymethyl, methoxymethyl.

Substituted and unsubstituted “haloalkyl” are used herein denotes analkyl unit having a hydrogen atom substituted by one or more halogenatoms, for example, trifluoromethyl, 1,2-dicloroethyl, and3,3,3-trifluoropropyl.

The term “aryl” as used herein denotes cyclic organic units thatcomprise at least one benzene ring having a conjugated and aromaticsix-membered ring, non-limiting examples of which include phenyl (C₆),naphthylen-1-yl (C₁₀), naphthylen-2-yl (C₁₀). Aryl rings can have one ormore hydrogen atoms substituted by another organic or inorganic radical.Non-limiting examples of substituted aryl rings include: 4-fluorophenyl(C₆), 2-hydroxyphenyl (C₆), 3-methylphenyl (C₆), 2-amino-4-fluorophenyl(C₆), 2-(N,N-diethylamino)phenyl (C₆), 2-cyanophenyl (C₆),2,6-di-tert-butylphenyl (C₆), 3-methoxyphenyl (C₆),8-hydroxynaphthylen-2-yl (C₁₀), 4,5-dimethoxynaphthylen-1-yl (C₁₀), and6-cyanonaphthylen-1-yl (C₁₀).

The term “heteroaryl” denotes an organic unit comprising a five or sixmembered conjugated and aromatic ring wherein at least one of the ringatoms is a heteroatom selected from nitrogen, oxygen, or sulfur. Theheteroaryl rings can comprise a single ring, for example, a ring having5 or 6 atoms wherein at least one ring atom is a heteroatom not limitedto nitrogen, oxygen, or sulfur, such as a pyridine ring, a furan ring,or thiofuran ring.. A “heteroaryl” can also be a fused multicyclic andheteroaromatic ring system having wherein at least one of the rings isan aromatic ring and at least one atom of the aromatic ring is aheteroatom including nitrogen, oxygen, or sulfur

The following are non-limiting examples of heteroaryl rings according tothe present disclosure:

The term “heterocyclic” denotes a ring system having from 3 to 10 atomswherein at least one of the ring atoms is a heteroatom not limited tonitrogen, oxygen, or sulfur. The rings can be single rings, fused rings,or bicyclic rings. Non-limiting examples of heterocyclic rings include:

All of the aforementioned heteroaryl or heterocyclic rings can beoptionally substituted with one or more substitutes for hydrogen asdescribed herein further.

Throughout the description of the present disclosure the terms havingthe spelling “thiophene-2-yl and thiophene-3-yl” are used to describethe heteroaryl units having the respective formulae:

whereas in naming the compounds of the present disclosure, the chemicalnomenclature for these moieties are typically spelled “thiophen-2-yl andthiophen-3-yl” respectively. Herein the terms “thiophene-2-yl andthiophene-3-yl” are used when describing these rings as units ormoieties which make up the compounds of the present disclosure solely tomake it unambiguous to the artisan of ordinary skill which rings arereferred to herein.

The following are non-limiting examples of units which can substitutefor hydrogen atoms on a hydrocarbyl or other unit:

-   -   i) linear, branched, or cyclic alkyl, alkenyl, and alkynyl; for        example, methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl        (C₃), cyclopropyl (C₃), propylen-2-yl (C₃), propargyl (C₃),        n-butyl (C₄), iso-butyl (C₄), sec-butyl (C₄), tert-butyl (C₄),        cyclobutyl (C₄), n-pentyl (C₅), cyclopentyl (C₅), n-hexyl (C₆),        and cyclohexyl (C₆);    -   ii) substituted or unsubstituted aryl; for example, phenyl,        2-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 2-aminophenyl,        3-hydroxyphenyl, 4-trifluoromethylphenyl, and biphenyl-4-yl;    -   iii) substituted or unsubstituted heterocyclic; examples of        which are provided herein below;    -   iv) substituted or unsubstituted heteroaryl; examples of which        are provided herein below;    -   v) —(CR^(12a)R^(12b))_(q)OR¹¹; for example, —OH, —CH₂OH, —OCH₃,        —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vi) —(CR^(12a)R^(12b))_(q)C(O)R¹¹; for example, —COCH₃,        —CH₂COCH₃, —OCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   vii) —(CR^(12a)R^(12b))_(q)C(O)OR¹¹; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   viii) —(CR^(12a)R^(12b))_(q)OC(O)N(R¹¹)₂; for example, —CONH₂,        CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   ix) —(CR^(12a)R^(12b))_(q)OC(O)N(R¹¹)₂; for example, —OC(O)NH₂,        —CH₂OC(O)NH₂, —OC(O)NHCH₃, —CH₂OC(O)NHCH₃, —OC(O)N(CH₃)₂, and        —CH₂OC(O)N(CH₃)₂;    -   x) (CR^(12a)R^(12b))_(q)N(R¹¹)₂; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃), —CH₂NHCH₃, —CH₂N(CH₃)₂, and        —CH₂NH(CH₂CH₃);    -   xi) halogen: —F, —Cl, —Br, and —I;    -   xii) —CH_(m)X_(n); wherein X is halogen, m is from 0 to 2,        m+n=3; for example, —CH₂F, —CHF₂, —CF₃, —CCl₃, or —CBr₃;    -   xiii) —(CR^(12a)R^(12b))_(q)CN; for example; —CN, —CH₂CN, and        —CH₂CH₂CN;    -   xiv) —(CR^(12a)R^(12b))_(q)NO₂; for example; —NO₂, —CH₂NO₂, and        —CH₂CH₂NO₂;    -   xv) —(CR^(12a)R^(12b))_(q)SO₂R¹¹; for example, —SO₂H, —CH₂SO₂H,        —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xvi) —(CR^(12a)R^(12b))_(q)SO₃R¹¹; for example, —SO₃H, —CH₂SO₃H,        —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;    -   xvii) hydroxyl groups or thiol groups,    -   xviii) amino groups, monosubstituted amino, or disubstituted        amino, wherein each R¹¹ is independently hydrogen, substituted        or unsubstituted C₁-C₄ linear, branched, or cyclic alkyl; or two        R¹¹ units can be taken together to form a ring comprising 3-7        atoms; R^(12a) and R^(12b) are each independently hydrogen or        C₁-C₄ linear or branched alkyl; the index q is from 0 to 4.

The compounds and compositions recited herein can have a number ofutilities, and address several unmet medical needs, inter alia;

-   1) Providing compositions effective as inhibitors of human protein    prolyl hydroxylase, thereby stimulating an angiogenic response in    human tissue, thereby providing a method for increasing blood flow,    oxygen delivery and energy utilization in ischemic tissues;-   2) Providing compositions effective as human protein HIF-1α prolyl    hydroxylase inhibitors, and thereby increasing the concentration of    HIF-1α leading to greater activation and sustaining the of various    biological pathways that are the normal response to cellular    hypoxia;-   3) Providing compositions effective in stimulating an erythropoietic    (EPO) response in cells and thereby enhancing the maintenance of red    blood cells by controlling the proliferation and differentiation of    erythroid progenitor cells into red blood cells;-   4) Providing compositions effective in stimulating an angiogenic    response and thereby increasing the number and density of blood    vessels and thus alleviating the adverse consequences of    hypertension and diabetes, inter alia, claudication, ischemic    ulcers, accelerated hypertension, and renal failure;-   5) Providing compositions that activate Vascular Endothelial Growth    Factor (VEGF) gene transcription in hypoxic cells thus increasing    stimulus of important biological responses, inter alia,    vasodilation, vascular permeability, and endothelial cell migration    and proliferation.

Therefore, these and other unmet medical needs are resolved by theHIF-1α prolyl hydroxylase inhibitors of the present disclosure, whichare capable of regulating blood flow, oxygen delivery and energyutilization in ischemic tissues that are caused by insufficientregulation of HIF-1α prolyl hydroxylase. Those of skill in the art willalso recognize that inhibition of HIF-1α prolyl hydroxylase enzymes willhave other positive medical effects on human tissue and the alleviationof symptoms and disease states other than those symptoms or diseasesstates that are specifically pointed out in the present disclosure.However, as greater details arise concerning disease states andconditions related to the angiogenic process, these yet undisclosed oryet unknown conditions will be positively affected by compositions whichstimulate the body own response to hypoxia and other low blood oxygenconditions.

For the purposes of the present disclosure the terms “compound,”“analog,” and “composition of matter” stand equally well for the HIF-1αprolyl hydroxylase enzyme inhibitors described herein, including allenantiomeric forms, diastereomeric forms, salts, and the like, and theterms “compound,” “analog,” and “composition of matter” are usedinterchangeably throughout the present specification.

The compounds disclosed herein include all salt forms, for example,salts of both basic groups, inter alia, amines, as well as salts ofacidic groups, inter alia, carboxylic acids. The following arenon-limiting examples of anions that can form pharmaceuticallyacceptable salts with basic groups: chloride, bromide, iodide, sulfate,bisulfate, carbonate, bicarbonate, phosphate, formate, acetate,propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate,succinate, tartrate, fumarate, citrate, and the like. The following arenon-limiting examples of cations that can form pharmaceuticallyacceptable salts of the anionic form of acidic substituent groups on thecompounds described herein: sodium, lithium, potassium, calcium,magnesium, zinc, bismuth, and the like.

The HIF-1α prolyl hydroxylase inhibitor compounds described herein aresubstituted aryl or heteroaryl amides, having the core structure shownin Formula (I) below.

wherein X can be N or CH; L is an organic linking unit as furtherdescribed, below, and Y, R, R¹ and R² can be any of the units furtherdescribed below.

When X is a nitrogen atom the compounds of the present disclosure are2-amidopyridines and when X is CH the compounds of the presentdisclosure are arylamides, as shown below:

R and R¹ are optional substituent groups that can be independentlychosen from a wide variety of inorganic (hydrogen, hydroxyl, amino,halogen or the like) or organic substituent units, such as alkyls,cycloalkyls, heterocyclic, heteroaryls, and the like, wherein suchsubstituent units can optionally have from 1 to 12 carbon atoms, or 1 to10 carbon atoms, or 1 to six carbon atoms. In many aspects of theinvention, R and R¹ can each be independently a chosen from:

-   -   i) hydrogen;    -   ii) substituted or unsubstituted phenyl; and    -   iii) substituted or unsubstituted heteroaryl.        wherein the optional substitutent units for the phenyl and        heteroaryl rings can be chosen from a wide variety of inorganic        and C₁-C₄ organic radicals, and there are typically zero, one,        two, or three of such substituent groups. In many such aspects,        one, two, or three substituentsfor the above-mentioned phenyl        and heteroaryl rings can be independently selected from:    -   i) C₁-C₄ linear, branched, or cyclic alkyl;    -   ii) C₁-C₄ linear, branched, or cyclic alkoxy;    -   iii) C₁-C₄ linear, branched, or cyclic haloalkyl;    -   iv) halogen;    -   v) —CN;    -   vi) —NHC(O)R⁴    -   vii) —C(O)NR^(5a)R^(5b);    -   viii) heteroaryl; or    -   ix) two substitutions can be taken together to form a fused ring        having from 5 to 7 atoms;        wherein the above-mentioned R⁴ unit can be hydrogen or a C₁-C₄        linear, branched, or cyclic alkyl; and wherein the R^(5a) and        R^(5b) units can be independently selected from:    -   i) hydrogen;    -   ii) C₁-C₄ linear, branched, or cyclic alkyl; or    -   iii) R^(5a) and R^(5b) can be taken together to form a ring        having from 3 to 7 atoms.

In some aspects of the compounds of Formula (I), the R units can bechosen from substituted or unsubstituted phenyl; or substituted orunsubstituted heteroaryls; and the R¹ units are hydrogen.

In other aspects of the compounds of Formula (I), R can be a substitutedor unsubstituted phenyl, having one, two, or three optional inorganic ororganic substitutents, which in some embodiments are chosen from:

-   -   i) C₁-C₄ linear, branched, or cyclic alkyl;    -   ii) C₁-C₄ linear, branched, or cyclic alkoxy;    -   iii) C₁-C₄ linear, branched, or cyclic haloalkyl;    -   iv) halogen; or    -   v) —CN.

Non-limiting examples of R units include 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl,3-ethylphenyl, 4-ethylphenyl, 2-iso-propylphenyl, 3-iso-propylphenyl,4-iso-propylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl,3-ethoxyphenyl, 4-ethoxyphenyl, 2-iso-propoxyphenyl,3-iso-propoxyphenyl, 4-iso-propoxyphenyl, 2-cyanophenyl, 3-cyanophenyl,4-cyanophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, and4-trifluoromethylphenyl.

In additional aspects of the compounds of Formula (I) the R units canhave the formula —NH(C(O)R⁴ wherein R⁴ is C₁-C₄ linear, branched, orcyclic alkyl. Non limiting examples of such R units include:

-   -   i) —NH(C(O)CH₃;    -   ii) —NH(C(O)CH₂CF1₃;    -   ii) —NH(C(O)CH₂CH₂CH₃;

ii) —NH(C(O)CH(CH₃)₂;

-   -   ii) —NH(C(O)(cyclopropyl); and    -   ii) —NH(C(O)CH₂CH₂CH₂CH₃.

In additional aspects of the compounds of Formula (I), the R units canhave the formula:

wherein R¹⁰ has the formula —C(O)NR^(5a)R^(5b); wherein R^(5a) andR^(5b) can be independently selected from hydrogen, C₁-C₄ linear orbranched alkyls, or R^(5a) and R^(5b) are taken together to from a ringhaving 5 or 6 atoms. In some such aspects, the R¹⁰ units can have theformula: —C(O)NR^(5a)R^(5b) wherein R^(5a) and R^(5b) are eachindependently selected from hydrogen, methyl, ethyl, n-propyl,iso-propyl, and cyclopropyl. Non-limiting examples of such R¹⁰ unitsinclude:

-   -   i) —C(O)NH₂;    -   ii) —C(O)NHCH₃;    -   iii) —C(O)N(CH₃)₂;    -   iv) —C(O)NH(CH₂CH₃);    -   v) —C(O)N(CH₂CH₃)₂;    -   vi) —C(O)N(CH₃)(CH₂CH₃).    -   vii) —C(O)NH(CH₂CH₂CH₃);    -   viii) —C(O)N(CH₂CH₂CH₃)₂;    -   ix) —C(O)NH[CH(CH₃)₂];    -   x) —C(O)N[CH(CH₃)₂]₂;    -   xi) —C(O)N(CH₂CH₂CH₃)[CH(CH₃)₂]; and    -   xii) —C(O)NH(cyclopropyl).

In additional aspects of the compounds of Formula (I), R^(5a) and R^(5b)together to form a ring having 5 or 6 ring atoms, non-limiting examplesof R¹⁰ units are heteroaryl units chosen from pyrrolidin-1-yl,piperidin-1-yl, piperazin-1-yl, and morpholin-4-yl.

In additional aspects of the compounds of Formula (I), the R¹⁰ units canbe heteroaryl units, non limiting examples of which are thiazol-2-yl,thiazol-4-yl, 1,2,3,4-tetrazol-5-yl, [1,2,4]triazol-5-yl, imidazol-2-yl,furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl,1,2,3,4-tetrazol-5-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl,furan-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, isoquinolin-1-yl, isoquinolin-3-yl, andisoquinolin-4-yl.

In additional aspects of the compounds of Formula (I), the R units caninclude substituted phenyl units wherein two substitutions can be takentogether to form a fused ring having from 5 to 7 ring atoms, for examplea 2,3-dihydro-benzo[1,4]dioxin-6-yl ring which would provide a compoundhaving the formula:

Other examples of R include units wherein R is hydrogen and R¹ ishydrogen.

wherein R², X, Y, L, and R⁹ can be independently chosen in any manner asotherwise taught herein with respect to the compounds of Formula (I).

As described previously above, the R¹ substituents for compounds ofFormula (I) can be chosen from a wide variety of inorganic and organicunits. In some embodiments, R¹ is a phenyl ring, which can optionally besubstituted with 1, 2, or 3 substituent units, independently selectedfrom inorganic or C₁-C₄ organic units. In some are chosen from:

-   -   i) C₁-C₄ linear, branched, or cyclic alkyl;    -   ii) C₁-C₄ linear, branched, or cyclic alkoxy;    -   iii) C₁-C₄ linear, branched, or cyclic haloalkyl;    -   iv) halogen; or    -   v) —CN.

Non-limiting examples of R¹ include 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl,3-ethylphenyl, 4-ethylphenyl, 2-iso-propylphenyl, 3-iso-propylphenyl,4-iso-propylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl,3-ethoxyphenyl, 4-ethoxyphenyl, 2-iso-propoxyphenyl,3-iso-propoxyphenyl, 4-iso-propoxyphenyl, 2-cyanophenyl, 3-cyanophenyl,4-cyanophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, and4-trifluoromethylphenyl.

Another example of R¹ units includes compounds wherein R is hydrogen andR¹ units are hydrogen.

In some aspects of the compounds of Formula (I), R is hydrogen and R¹ isa substituted or unsubstituted phenyl, wherein the substitutions arechosen from:

-   -   i) C₁-C₄ linear, branched, or cyclic alkyl;    -   ii) C₁-C₄ linear, branched, or cyclic alkoxy;    -   iii) C₁-C₄ linear, branched, or cyclic haloalkyl;    -   iv) halogen; and    -   v) —CN.

In connection with the compounds of Formula (I), Y is a unit that can bechosen from a wide variety of inorganic units, such as H, —OH, —NH₂, ora halogen, and C₁-C₄ organic units. For example, Y can be chosen from:

-   -   i) hydrogen;    -   ii) —OR³, wherein R³ is hydrogen, or a lower alkyl, such as        methyl, or ethyl.

In connection with the compounds of Formula (I), the R² units can bechosen from a wide variety of inorganic units, such as —OH, or —NH₂units, or a variety of organic units.

In some aspects fo the compounds of the invention, R² is chosen from:

-   -   i) —OR⁶; or    -   ii) —NR^(7a)R^(7b);        wherein R⁶ is hydrogen or C₁-C₄ linear, branched, or cyclic        alkyl; and R^(7a) and R^(7b)) are each independently chosen        from:    -   i) hydrogen;    -   ii) C₁-C₄ linear, branched, or cyclic alkyl; or    -   iii) R^(7a) and R^(7b) can be taken together to form a ring        having from 3 to 7 atoms.

In certain favored aspects of the invention the R² units are hydroxyl(—OH) wherein the compounds are carboxylic acids, or may also be presentin the form of a salt as the corresponding hydroxyl/carboxylate anion,i.e. R2 can be a —O^(—) unit, so as to form a compound having acarboxylate group, as shown below.

wherein R, R¹, R², X, Y, L, and R⁹ can be independently chosen in anymanner as otherwise taught herein with respect to the compounds ofFormula (I).

Another example of R² includes compounds wherein R⁶ is C₁-C₄ linear,branched, or cyclic alkyl providing R² units which are alkoxy whereinthe compounds formed are organic esters having C₁-C₄ linear, branched,or cyclic alkyl groups. Non-limiting examples of R² units are:

-   -   i) —OCH₃;    -   ii) —OCH₂CH₃; and    -   iii) —OCH₂CH₂CH₃.

Yet further examples of R² units include compounds wherein R² has theformula —NR^(7a)R^(7b); and R^(7a) and R^(7b) are each independentlychosen from:

-   -   i) hydrogen; and    -   ii) C₁-C₄ linear, branched, or cyclic alkyl.

-   Non-limiting examples of R² units include:    -   i) —NH₂;    -   ii) —NHCH₃;    -   iii) —N(CH₃)₂;    -   iv) —NH(CH₂CH₃);    -   v) —N(CH₂CH₃)₂;    -   vi) —N(CH₃)(CH₂CH₃).    -   vii) —NH(CH₂CH₂CH₃);    -   viii) —N(CH₂CH₂CH₃)₂;    -   ix) —NH[CH(CH₃)₂];    -   x) —N[CH(CH₃)₂]₂;    -   xi) —N(CH₂CH₂CH₃)[CH(CH₃)₂]; and    -   xii) —NH(cyclopropyl).

A yet further example of R² units includes compounds wherein R² has theformula —NR^(7a)R^(7b); and R^(7a) and R^(7b) are taken together to forma ring having from 3 to 7 atoms, wherein the non- limiting examples ofR² units include aziridin-1-yl, axetidin-1-yl, pyrolidin-1-yl,piperidin-1-yl, piperazin-1-yl, and morpholin-4-yl.

In connection with the compounds of Formula (I), L is a unit that linksthe nitrogen atom of the carboxyamide group to the neighboring carbonylgroup. L is typically a C₁-C₆ or C₁-C₄ organic linking unit. In someembodiments, L comprises a one or more optionally substituted methyleneunits having the formula:

—[C(R^(8a)R^(8b))]_(y)—;

wherein R^(8a) and R^(8b) are each independently hydrogen, C₁-C₆ linearor branched alkyl, or phenyl; and the index y is from 1 to 4.

An example of L units includes units wherein R^(8a) and R^(8b) are bothhydrogen and the index n is equal to 1, the L unit has the formula:

—CH₂—

and are referred to herein as methylene linking units, so as to formcompounds having the structure shown below:

wherein R, R¹, R², X, Y, and R⁹ can be independently chosen in anymanner as otherwise taught herein with respect to the compounds ofFormula (I).

Another example of L units includes units wherein R^(8a) and R^(8b) areeach hydrogen or methyl and the index n is equal to 1, these unitshaving the formula:

—CH(CH₃)— or —C(CH₃)₂—.

A further example of L units includes units wherein all R^(8a) andR^(8b) units are hydrogen and the index n is equal to 2, these unitshaving the formula:

—CH₂CH₂—

and are referred to herein as ethylene linking units.

In connection with the compounds of Formula I, the R⁹ substituent forthe amide nitrogen atom can be hydrogen or a C₁-C₄ organic substituent,such as a C₁-C₄ alkyl group, such as methyl, or a C_(l)-C₄ haloalkyl,such as a trifluoromethyl group.

The compounds of Formula (I) can be organized into several categoriesfor the strictly non-limiting purpose of describing alternatives forsynthetic strategies for the preparation of subgenera of compoundswithin the scope of Formula (I) that are not expressly exemplifiedherein. This mental organization into categories does not imply anythingwith respect to increased or decreased biological efficacy with respectto any of the compounds or compositions of matter described herein.

One such subgenus of the compounds of Formula (I) relates to compoundshaving the formula:

which can be more specifically described by methyl ester compoundshaving the formula:

wherein R units can be substituted or unsubstituted phenyl, non-limitingexamples of which are described in Table I herein below.

TABLE I No. R 1 2-fluorophenyl 2 3-fluorophenyl 3 4-fluorophenyl 42-chlorophenyl 5 3-chlorophenyl 6 4-chlorophenyl 7 2-cyanophenyl 83-cyanophenyl 9 4-cyanophenyl 10 2-methylphenyl 11 3-methylphenyl 124-methylphenyl 13 2-ethylphenyl 14 3-ethylphenyl 15 4-ethylphenyl 162-methoxyphenyl 17 3-methoxyphenyl 18 4-methoxyphenyl 19 2-ethoxyphenyl20 3-ethoxyphenyl 21 4-ethoxyphenyl 22 2-iso-propoxyphenyl 233-iso-propoxyphenyl 24 4-iso-propoxyphenyl 25 2-carbamoylphenyl 263-carbamoylphenyl 27 4-carbamoylphenyl 28 2-(aziridine-1-carbonyl)phenyl29 3-(aziridine-1-carbonyl)phenyl 30 4-(aziridine-1-carbonyl)phenyl 312-(azetidine-1-carbonyl)phenyl 32 3-(azetidine-1-carbonyl)phenyl 334-(azetidine-1-carbonyl)phenyl 34 2-(pyrrolidine-1-carbonyl)phenyl 353-(pyrrolidine-1-carbonyl)phenyl 36 4-(pyrrolidine-1-carbonyl)phenyl 372-(piperidine-1-carbonyl)phenyl 38 3-(piperidine-1-carbonyl)phenyl 394-(piperidine-1-carbonyl)phenyl 40 2-(acetylamino)phenyl 413-(acetylamino)phenyl 42 4-(acetylamino)phenyl 432-(ethanecarbonylamino)phenyl 44 3-(ethanecarbonylamino)phenyl 454-(ethanecarbonylamino)phenyl 46 2-(cyclopropanecarbonylamino)phenyl 473-(cyclopropanecarbonylamino)phenyl 484-(cyclopropanecarbonylamino)phenyl

Such compounds can be prepared by the procedure outlined in Scheme I andfurther described in Example 1 herein below.

EXAMPLE 1 {[5-(3-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino }acetic acid methyl ester (6)

Preparation of 3,5-bis-benzyloxy-pyridine-2-carbonitrile (1): To an 80mL microwave pressure vessel is charged dry THF (30 mL) and benzylalcohol (6.32 mL, 61.1 mmol). The solution is cooled to 0° C. and sodiumhydride (2.44 g of a 60% dispersion in mineral oil, 61.1 mmol) is addedin portions. The reaction mixture is gradually allowed to warm to roomtemperature with efficient stirring until the evolution of hydrogen gasceases. The solution is re-cooled to 0° C. and3,5-dichloro-2-cyanopyridine (5.00 g, 29.1 mmol) is added, and thesolution is transferred to an unfocussed Mars 5 CEM microwave reactor to190° C., 300 W and held for 5 hours. The reaction mixture is quenchedwith H₂O, concentrated under reduced pressure, diluted with EtOAc andwashed with 2M Na₂CO₃, H₂O and saturated aqueous NaCl. The organic layeris dried (MgSO₄), filtered and concentrated under reduced pressure togive a brown solid. The crude solid is purified over silica(EtOAc:heptane, gradient 1:1 to 1:0) to afford 8.6 g (94% yield) of thedesired compound as an orange solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.96(1H, d, J=2.2 Hz), 7.25-7.37 (10 H, m), 6.78 (1H, d, J=2.2 Hz), 5.10(2H, s), 5.03 (2H, s). HPLC-MS: m/z 317 [M+H]⁺.

Preparation of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid (2): To asolution of 3,5-bis-benzyloxy-pyridine-2-carbonitrile, 1, (26.0 g, 82.3mmol) in MeOH (217 mL) is added 30% w/v sodium hydroxide (320 mL) andthe reaction mixture is refluxed for 16 hours. The solvent is removedunder reduced pressure and the resulting suspension is acidified withconc. HCl until the pH is between 1 and 2. The precipitate that resultsis collected by filtration, washed with H₂O (10 mL) and dried overnightin a vacuum oven to afford 30 g (quantitative) of the desired product asthe hydrochloride salt. ¹H NMR (250 MHz, DMSO-d₆) δ ppm 8.02 (1H, d,J=2.4 Hz), 7.29-7.53 (11 H, m), 5.96 (1H, br s), 5.28 (4H, s). HPLC-MS:m/z 336 [M+H]⁺.

Preparation of [(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-aceticacid methyl ester (3): To a solution of3,5-bis-benzyloxy-pyridine-2-carboxylic acid HCl, 2, (8.06 g, 21.7 mmol)in DMF (100 mL) at 0° C. under N₂ is added diisopropylethylamine (11.35mL, 65.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI)(6.23 g, 32.6 mmol) and 1-hydroxybenzotriazole (HOBt) (0.294 g, 2.2mmol). The solution is stirred for 5 minutes and glycine methyl esterhydrochloride (4.09 g, 32.6 mmol) is added. The reaction is allowed towarm slowly to room temperature and stirred 3 days. The reaction volumeis partially concentrated under reduced pressure then diluted with EtOAcand washed with saturated aqueous NaHCO₃ and saturated aqueous NaCl. Theorganic layer is dried (MgSO₄), filtered and concentrated under reducedpressure to afford a yellow oil that is purified over silica(EtOAc:heptane gradient 1:1 to 1:0) to afford 3.5 g (40% yield) of thedesired product as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.12 (1H,t, J=4.9 Hz), 7.95 (1H, d, J=1.8 Hz), 7.38-7.44 (2H, m), 7.22-7.35 (8 H,m), 6.85 (1H, d, J=2.6 Hz), 5.14 (2H, s), 5.03 (2H, s), 4.18 (2H, d,J=5.5 Hz), 3.69 (3H, s). HPLC-MS: m/z 407 [M+H]⁺.

Preparation of [(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-acetic acidmethyl ester (4): To a solution[(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-acetic acid methyl ester(3.50 g, 8.62 mmol) in MeOH (100 mL) is added 10% Pd/C (0.350 g, 0.862mmol) and the reaction mixture stirred under an atmosphere of H₂ at roomtemperature for 16 hours.

The suspension is filtered through Celite™ and the filtrate concentratedunder reduced pressure. The crude material is purified over silica(MeOH:CH₂Cl₂ gradient 1% to 5%) to afford 1.95 g (quantitative yield) ofthe desired compound as an off-white solid. ¹H NMR (250 MHz, MeOD) δ ppm7.62 (1H, d, J=2.4 Hz), 6.53 (1H, d, J=2.4 Hz), 4.04 (2H, s), 3.64 (3H,s). HPLC-MS: m/z 227 [M+H]⁺.

Preparation of[(3-hydroxy-5-trifluoromethanesulfonyloxy-pyridine-2-carbonyl)-amino]-aceticacid methyl ester (5): To a solution of[(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid methyl ester, 4,(1.95 g, 8.62 mmol) in MeOH (60 mL) is added diisopropylethylamine(DIPEA) (1.62 mL, 9.3 mmol). The mixture is cooled to 0° C. and N-phenyltrifluoromethansulfonimide (3.32 g, 9.3 mmol) is added. The resultingsolution is slowly warmed to room temperature and stirred for anadditional 16 hours. The solvent is removed under reduced pressure andthe crude material is purified over silica (EtOAc:hexane 1:4) to afford2.27 g (73% yield) of the desired product as an off-white solid. ¹H NMR(400 MHz, CDCl₃) δ ppm 12.17 (1H, s), 8.27 (1H, t, J=5.5 Hz), 8.08 (1 H,d, J=2.2 Hz), 7.28 (1H, d, J=2.2 Hz), 4.24 (2H, d, J=5.5 Hz), 3.82 (3H,s). HPLC-MS: m/z 359 [M+H]⁺.

Preparation of{[5-(3-chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acidmethyl ester (6): To a degassed solution of[(3-hydroxy-5-trifluoromethane-sulfonyloxy-pyridine-2-carbonyl)-amino]-aceticacid methyl ester, 5, (0.30 g, 0.84 mmol) in 1,4-dioxane (10 mL) at roomtemperature under N₂ is added 3-chlorophenylboronic acid (0.196 g, 1.26mmol), Pd(dppf)Cl₂ (0.068 g, 0.0084 mmol) and K₃PO₄ (0.195 g, 0.92mmol). The resulting suspension is heated in a sealed tube at 85° C. for16 hours. After this time, the mixture is cooled to room temperature andconcentrated under reduced pressure. The residue is then treated with 1MHCl (1 mL) and diluted with EtOAc. The organic layer is separated,washed with H₂O, saturated aqueous NaCl and concentrated under reducedpressure. The crude material is purified over silica (EtOAc:heptane3:7). The resulting solid can be crystallized from EtOAc/heptane toafford 0.143g (53% yield) of the desired compound as a colorless solid.¹H NMR (400 MHz, CDCl₃) δ ppm 11.77 (1H, s), 8.36 (1H, t, J=5.7 Hz),8.24 (1H, d, J=1.8 Hz), 7.50-7.53 (1H, m), 7.39-7.42 (2H, m), 7.34-7.37(2H, m), 4.20 (2H, d, J=5.9 Hz), 3.76 (3H, s). HPLC-MS: m/z.

The procedure outlined in Scheme I can be modified by substituting instep (f) other reagents for 3-chlorophenylboronic acid. Non-limitingexamples include 4-chlorophenylboronic acid, 2-chlorophenylboronic acid,2-fluorophenylboronic acid, 3-fluorophenylboronic acid,4-fluorophenylboronic acid, 2-methylphenylboronic acid,3-methylphenylboronic acid, and 4-methylphenylboronic acid.

The following are further non-limiting examples of compounds encompassedwithin first aspect of Category I of the present disclosure.

{[5-(4-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acidmethyl ester: ¹H NMR (400 MHz, CDCl₃) δ ppm 11.77 (1H, s), 8.36 (1H, t,J=5.5 Hz), 8.23 (1H, d, J=1.8 Hz), 7.44-7.49 (2H, m), 7.38-7.42 (3H, m),4.20 (2H, d, J=5.9 Hz), 3.76 (3H, s). HPLC-MS: m/z 321 [M+H]⁺.

{[5-(2-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acidmethyl ester: ¹H NMR (400 MHz, MeOD) δ ppm 8.10 (1H, d, J=1.8 Hz), 7.46(1H, dd, J=7.5, 2.4 Hz), 7.30-7.35 (4H, m), 4.11 (2H, s), 3.68 (3H, s).HPLC-MS: m/z 321 [M+H]⁺.

{[5-(4-Fluorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acidmethyl ester: ¹H NMR (250 MHz, CDCl₃) δ ppm 11.88 (1H, s), 8.48 (1H, t,J=5.6 Hz), 8.33 (1H, d, J=2.1 Hz), 7.55-7.65 (2H, m), 7.49 (1H, d, J=2.1Hz), 7.17-7.27 (2H, m), 4.28-4.32 (2H, m), 3.86 (3H, s). HPLC-MS: m/z305 [M+H]⁺.

[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-acetic acidmethyl ester: ¹H NMR (400 MHz, CDCl₃) δ ppm 11.72 (1H, s), 8.36 (1H, t,J=5.1 Hz), 8.26 (1H, d, J=1.8 Hz), 7.43 (2H, d, J=8.0 Hz), 7.40 (1H, d,J=1.8 Hz), 7.23 (2H, d, J=8.1 Hz), 4.19 (2H, d, J=5.9 Hz), 3.75 (3H, s),2.35 (3H, s). HPLC-MS: m/z 301 [M+H]⁺.

{[3-Hydroxy-5-(4-is opropylphenyl)-pyridine-2-carbonyl]-amino}-aceticacid methyl ester: ¹H NMR (250 MHz, CDCl₃) δ ppm 11.88 (1H, s), 8.54(1H, t, J=5.6 Hz), 8.38 (1H, d, J=1.8 Hz), 7.55-7.60 (2H, m), 7.54 (1H,d, J=2.1 Hz), 7.36-7.42 (2H, m), 4.30 (2H, d, J=5.8 Hz), 3.85 (3H, s),2.93-3.07 (1H, m), 1.33 (6 H, d, J=7.0 Hz). HPLC-MS: m/z 329 [M+H]⁺.

{[5-(4-Ethylphenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acidmethyl ester: ¹H NMR (250 MHz, CDCl₃) δ ppm 11.86 (1H, s), 8.51 (1H, t,J=5.8 Hz), 8.37 (1H, d, J=1.8 Hz), 7.56 (2H, d, J=8.2 Hz), 7.53 (1H, d,J=1.8 Hz), 7.36 (2H, d, J=8.5 Hz), 4.30 (2H, d, J=5.8 Hz), 3.85 (3H, s),2.75 (2H, q, J=7.6 Hz), 1.31 (3H, t, J=7.6 Hz). HPLC-MS: m/z 315 [M+H]⁺.

{[3-Hydroxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-amino}-aceticacid methyl ester: ¹H NMR (250 MHz, CDCl₃) δ ppm 11.91 (1H, s), 8.48(1H, t, J=6.1 Hz), 8.37 (1H, d, J=1.8 Hz), 7.60-7.92 (4H, m), 7.54 (1H,d, J=2.1 Hz), 4.31 (2H, d, J=5.8 Hz), 3.86 (3H, s). HPLC-MS: m/z 355[M+H]⁺.

{[5-(4-Cyanophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acidmethyl ester: ¹H NMR (400 MHz, CDCl₃) δ ppm 11.83 (1H, s), 8.36 (1H, t,J=5.12 Hz), 8.26 (1H, d, J=1.83 Hz), 7.70-7.75 (2H, m), 7.62-7.66 (2H,m), 7.43 (1H, d, J=1.83 Hz), 4.21 (2H, d, J=5.49 Hz), 3.76 (3H, s).HPLC-MS: m/z 312 [M+H]⁺.

{[5-(3-Cyanophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acidmethyl ester: ¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.30 (1H, s), 9.51 (1H,t, J=5.8 Hz), 8.55 (1H, d, J=1.8 Hz), 8.32 (1H, s), 8.14 (1H, d, J=8.5Hz), 7.89 (1H, d, J=7.8 Hz), 7.81 (1H, d, J=1.9 Hz), 7.68 (1H, t, J=7.8Hz), 4.06 (2H, d, J=6.1 Hz), 3.63 (3H, s). HPLC-MS: m/z 312 [M+H]⁺.

{[5-(3-Carbamoylphenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-aceticacid methyl ester: ¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.30 (1H, s), 9.54(1H, t, J=6.0 Hz), 8.61 (1H, d, J=1.8 Hz), 8.29 (1H, s), 8.18 (1H, brs), 7.98 (2H, t, J=8.1 Hz), 7.84 (1H, d, J=1.7 Hz), 7.62 (1H, t, J=7.8Hz), 7.53 (1H, br s), 4.12 (2H, d, J=6.0 Hz), 3.69 (3H, s). HPLC-MS: m/z330 [M+H]⁺.

({3-Hydroxy-5-[3-(pyrrolidine-1-carbonyl)-phenyl]-pyridine-2-carbonyl}-amino)-aceticacid methyl ester: ¹H NMR (250 MHz, CDCl₃) δ ppm 11.80 (1H, s), 8.44(1H, t, J=5.3 Hz), 8.35 (1H, s), 7.77 (1H, s), 7.47-7.70 (4H, m), 4.28(2H, d, J=5.7 Hz), 3.83 (3 H, s), 3.64-3.76 (2H, m), 3.42-3.55 (2H, m),1.84-2.07 (4H, m). HPLC-MS: m/z 384 [M+H]⁺.

({5-[3-(Cyclopropanecarbonyl-amino)-phenyl]-3-hydroxy-pyridine-2-carbonyl}-amino)-aceticacid methyl ester: ¹H NMR (250 MHz, CDCl₃) δ ppm 11.80 (1H, s), 8.45(1H, br s), 8.29 (1H, s), 7.65-7.88 (2H, m), 7.29-7.60 (4H, m),4.18-4.31 (3H, m), 3.83 (3H, s), 1.05-1.17 (2H, m), 0.81-0.98 (2H, m).HPLC-MS: m/z 370 [M+H]⁺.

The following heteroaryl substituted phenyl compound can be preparedfrom {[5-(3-cyano-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}aceticacid methyl ester by treatment with trimethylsilyl azide and di-butyltin oxide in DME and heating the mixture to 140° C., 150 W, 200 psi in amicrowave reactor.

({3-Hydroxy-5-[3-(2H-tetrazol-5-yl)-phenyl]-pyridine-2-carbonyl}-amino)-aceticacid methyl ester: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.33 (1H, s), 9.55(1H, t, J=6.1 Hz), 8.62 (1H, d, J=1.8 Hz), 8.43 (1H, s), 8.14 (1H, d,J=7.9 Hz), 8.05 (1H, d, J=8.1 Hz), 7.83 (1H, d, J=1.9 Hz), 7.76 (1H, t,J=7.8 Hz), 4.12 (2H, d, J=6.1 Hz), 3.69 (3 H, s). HPLC-MS: m/z 355[M+H]⁺.

For the purposes of describing synthetic methods, another mentalsubgenus of the compounds of Formula (I) have the formula:

wherein R units which are substituted or unsubstituted heteroaryl,non-limiting examples of which are described in Table II herein below.

TABLE II No. R 49 pyridin-2-yl 50 pyridin-3-yl 51 pyridin-4-yl 52pyrimidin-2-yl 53 pyrimidin-4-yl 54 pyrimidin-5-yl 55 isoquinolin-1-yl56 isoquinolin-3-yl 57 isoquinolin-4-yl 58 thiazol-2-yl 59 thiazol-4-yl60 1,2,3,4-tetrazol-5-yl 61 [1,2,4]triazol-5-yl 62 imidazol-2-yl 63furan-2-yl 64 furan-3-yl 65 thiophene-2-yl 66 thiophene-3-yl

The compounds encompassed within the compounds described immediatelyabove can be prepared by the procedure outlined in Scheme I anddescribed in Example 1 herein above.

The procedure outlined in Scheme I can be modified by substituting instep (f) other reagents for 3-chlorophenylboronic acid. Non-limitingexamples of substitutes include 3-(thiazol-2-yl)phenylboronic acid,3-(thiazol-4-yl)phenylboronic acid, 4-(thiazol-2-yl)phenylboronic acid,4-(thiazol-4-yl)phenylboronic acid, 3-(imidazol-2-yl)phenylboronic acid,4-(imidazol-2-yl)phenylboronic acid, 3-(furan-2-yl)phenylboronic acid,3-(furan-3-yl)phenylboronic acid, and 3-(thiophene-2-yl)phenylboronicacid.

The following are non-limiting examples of such compounds.

[(5-Hydroxy-[3,3′]bipyridinyl-6-carbonyl)-amino]-acetic acid methylester ¹H NMR (250 MHz, CDCl₃) δ ppm 11.80 (1H, s), 8.87 (1H, d, J=1.7Hz), 8.70 (1H, dd, J=4.8, 1.6 Hz), 8.45 (1H, t, J=5.8 Hz), 8.33 (1H, d,J=1.9 Hz), 7.91 (1H, ddd, J=8.0, 2.3, 1.7 Hz), 7.51 (1H, d, J=1.9 Hz),7.45 (1H, ddd, J=7.9, 4.8, 0.7 Hz), 4.28 (2H, d, J=5.8 Hz), 3.83 (3H,s). HPLC-MS: m/z 288 [M+H]⁺.

[(5′-Hydroxy-[2,3′]bipyridinyl-6′-carbonyl)-amino]-acetic acid methylester: ¹H NMR (250 MHz, CDCl₃) δ ppm 8.70-8.79 (2H, m), 8.49 (1H, t,J=5.8 Hz), 7.72-7.92 (3H, m), 7.31-7.39 (1H, m), 4.28 (2H, d, J=5.8 Hz),3.83 (3H, s). HPLC-MS: m/z 288 [M+H]⁺.

[(3-Hydroxy-5-pyrimidin-5-yl-pyridine-2-carbonyl)-amino]-acetic acidmethyl ester: ¹H NMR (250 MHz, CDCl₃) δ ppm 11.90 (1H, s), 9.32 (1H, s),9.00 (2H, s), 8.45 (1H, br s), 8.34 (1H, d, J=1.8 Hz), 7.53 (1H, d,J=1.8 Hz), 4.29 (2H, d, J=5.7 Hz), 3.84 (3H, s). HPLC-MS: m/z 289[M+H]⁺.

[(3-Hydroxy-5-isoquinolin-4-yl-pyridine-2-carbonyl)-amino]-acetic acidmethyl ester: ¹H NMR (250 MHz, CDCl₃) δ ppm 11.80 (1H, s), 9.38 (1H, brs), 8.51 (2H, t, J=5.7 Hz), 8.27 (1H, s), 8.13 (1H, d, J=7.2 Hz),7.67-7.93 (3H, m), 7.51(1H, s), 4.31(2H, d, J=5.7 Hz), 3.85 (3H, s).HPLC-MS: m/z 338 [M+H]⁺.

[(3-Hydroxy-5-thiazol-2-yl-pyridine-2-carbonyl)-amino]-acetic acidmethyl ester: ¹H NMR (250 MHz, CDCl₃) δ ppm 11.80 (1H, s), 8.67 (1H, d,J=1.8 Hz), 8.39 (1H, br s), 7.93 (1H, d, J=3.3 Hz), 7.78 (1H, d, J=1.7Hz), 7.43 (1H, d, J=3.2 Hz), 4.22 (2H, d, J=5.8 Hz), 3.78 (3H, s).HPLC-MS: m/z 294 [M+H]⁺.

Another mental subgenus of the compounds of Formula (I) encompassescompounds having the formula:

wherein R units which are substituted or unsubstituted phenyl,non-limiting examples of which are described in Table III herein below.

TABLE III No. R 67 2-fluorophenyl 68 3-fluorophenyl 69 4-fluorophenyl 702-chlorophenyl 71 3-chlorophenyl 72 4-chlorophenyl 73 2-cyanophenyl 743-cyanophenyl 75 4-cyanophenyl 76 2-methylphenyl 77 3-methylphenyl 784-methylphenyl 79 2-ethylphenyl 80 3-ethylphenyl 81 4-ethylphenyl 822-methoxyphenyl 83 3-methoxyphenyl 84 4-methoxyphenyl 85 2-ethoxyphenyl86 3-ethoxyphenyl 87 4-ethoxyphenyl 88 2-iso-propoxyphenyl 893-iso-propoxyphenyl 90 4-iso-propoxyphenyl 91 2-carbamoylphenyl 923-carbamoylphenyl 93 4-carbamoylphenyl 94 2-(aziridine-1-carbonyl)phenyl95 3-(aziridine-1-carbonyl)phenyl 96 4-(aziridine-1-carbonyl)phenyl 972-(azetidine-1-carbonyl)phenyl 98 3-(azetidine-1-carbonyl)phenyl 994-(azetidine-1-carbonyl)phenyl 100 2-(pyrrolidine-1-carbonyl)phenyl 1013-(pyrrolidine-1-carbonyl)phenyl 102 4-(pyrrolidine-1-carbonyl)phenyl103 2-(piperidine-1-carbonyl)phenyl 104 3-(piperidine-1-carbonyl)phenyl105 4-(piperidine-1-carbonyl)phenyl 106 2-(acetylamino)phenyl 1073-(acetylamino)phenyl 108 4-(acetylamino)phenyl 1092-(ethanecarbonylamino)phenyl 110 3-(ethanecarbonylamino)phenyl 1114-(ethanecarbonylamino)phenyl 112 2-(cyclopropanecarbonylamino)phenyl113 3-(cyclopropanecarbonylamino)phenyl 1144-(cyclopropanecarbonylamino)phenyl

The compounds described immediately above can be prepared by theprocedure outlined in Scheme II and described in Example 2.

EXAMPLE 2{[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid (7)

Preparation of{[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid(7): To a solution of{[5-(3-chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acidmethyl ester, 6, (0.163 g, 0.509 mmol) in THF (5 mL) is added 1M NaOH(1.5 ml, 1.27 mmol) and the reaction mixture stirred at room temperaturefor 1 hour. The solution is acidified using 1M HCl (3 mL), the solventremoved under reduced pressure and the resulting solid suspended inCHCl₃:iso-propanol (1:1), filtered and the filtrate dried (MgSO₄),filtered and re-concentrated under reduced pressure. The crude materialis triturated with a small amount of MeOH to afford 0.10 g (64% yield)of the desired product as a colorless solid. ¹H NMR (400 MHz, MeOD) δppm 8.31 (1H, d, J=1.8 Hz), 7.47 (2H, d, J=1.8 Hz), 7.30-7.65 (4H, m),4.07 (2H, s). HPLC-MS: m/z 307 [M+H]⁺.

The following are further non-limiting examples.

{[5-(4-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid: ¹HNMR (400 MHz, MeOD) δ ppm 8.33 (1H, d, J=1.5 Hz), 7.61 (2H, d, J=8.4Hz), 7.48 (1H, d, J=1.8 Hz), 7.42 (2H, d, J=8.4 Hz), 4.06 (2H, s).HPLC-MS: m/z 307 [M+H]⁺.

{[5-(2-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid: ¹HNMR (400 MHz, MeOD) δ ppm 8.10 (1H, d, J=1.8 Hz), 7.40-7.56 (1H, m),7.09-7.40 (4H, m), 4.07 (2H, s). HPLC-MS: m/z 307 [M+H]⁺.

{[5-(4-F luorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid:¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.39 (1H, br s), 9.38 (1H, t, J=6.2Hz), 8.53 (1H, d, J=2.1 Hz), 7.91 (2H, dd, J=8.8, 5.5 Hz), 7.74 (1H, d,J=2.1 Hz), 7.38 (2H, t, J=8.8 Hz), 4.02 (2H, d, J=6.4 Hz). HPLC-MS: m/z291 [M+H]⁺.

[(3-Hydroxy-5-(4-methylphenyl)pyridine-2-carbonyl)amino]-acetic acid: ¹HNMR (400 MHz, MeOD) δ ppm 8.40 (1H, s), 7.68 (1H, s), 7.53 (2H, d,J=8.42 Hz), 7.26 (2H, d, J=8.05 Hz), 4.10 (2H, s), 2.31 (3H, s).HPLC-MS: m/z 287 [M+H]⁺.

{[5-(4-Ethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid: ¹HNMR (250 MHz, DMSO-d₆) δ ppm 12.40 (1H, s), 9.35 (1H, t, J=6.1 Hz), 8.52(1H, d, J=2.1 Hz), 7.76 (2H, d, J=8.2 Hz), 7.71 (1H, d, J=1.8 Hz), 7.38(2H, d, J=8.2 Hz), 4.02 (2H, d, J=6.1 Hz), 2.68 (2H, q, J=7.6 Hz), 1.22(3H, t, J=7.5 Hz). HPLC-MS: m/z 301 [M+H]⁺.

{[3-Hydroxy-5-(4-isopropylphenyl)pyridine-2-carbonyl]amino}-acetic acid:¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.40 (1H, s), 9.36 (1H, t, J=6.2 Hz),8.52 (1H, d, J=1.8 Hz), 7.70 (2H, d, J=1.8 Hz), 7.76 (2H, d, J=8.2 Hz),7.41 (2H, d, J=8.2 Hz), 4.02 (2H, d, J=6.1 Hz), 2.97 (1H, m, J=7.0 Hz),1.25 (6 H, d, J=7.0 Hz). HPLC-MS: m/z [M+H]⁺ 315.

{[3-Hydroxy-5-(3-trifluoromethylphenyl)pyridine-2-carbonyl]amino}-acetic acid: ¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.42 (1H, br s), 9.41 (1H,t, J=6.4 Hz), 8.61 (1H, d, J=1.8 Hz), 8.10-8.22 (2H, m), 7.88 (1H, d,J=1.8 Hz), 7.73-7.86 (2H, m), 4.03 (2H, d, J=6.1 Hz). HPLC-MS: m/z 341[M+H]⁺.

{[5-(4-Cyanophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid: ¹HNMR (400 MHz, MeOD) δ ppm 8.38 (1H, d, J=1.8 Hz), 7.75-7.83 (4H, m),7.56 (1H, d, J=1.8 Hz), 4.06 (2H, s). HPLC-MS: m/z 298 [M+H]⁺.

{[5-(3-Cyanophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid: ¹HNMR (250 MHz, DMSO- d₆) δ ppm 12.40 (1H, s), 9.40 (1H, t, J=6.17 Hz),8.59 (1H, d, J=1.71 Hz), 8.37 (1H, s), 8.19 (1H, d, J=7.77 Hz), 7.93(1H, d, J=7.88 Hz), 7.86 (1H, d, J=1.94 Hz), 7.73 (1H, t, J=7.77 Hz),4.00 (2H, d, J=6.17 Hz). HPLC-MS: m/z 298 [M+H]⁺.

{[5-(5-Chloro-2-methylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-aceticacid: ¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.35 (1H, br s), 9.34 (1H, t,J=6.0 Hz), 8.17 (1H, d, J=1.8 Hz), 7.47 (1H, d, J=1.8 Hz), 7.33-7.45(3H, m), 3.95 (2H, d, J=5.9 Hz), 2.22 (3H, s). HPLC-MS: m/z 321 [M+H]⁺.

{[3-Hydroxy-5-(4-isopropoxyphenyl)pyridine-2-carbonyl]amino}-aceticacid: ¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.36 (1H, br s), 9.35 (1H, t,J=5.9 Hz), 8.50 (1H, d, J=1.8 Hz), 7.71 (1H, d, J=1.8 Hz), 7.27-7.46(3H, m), 7.02 (1H, d, J=8.5 Hz), 4.70-4.85 (1H, m), 4.01 (2H, d, J=6.1Hz), 1.29 (6 H, d, J=5.9 Hz). HPLC-MS: m/z 331 [M+H]⁺.

({5-[3-(Cyclopropanecarbonylamino)phenyl]-3-hydroxy-pyridine-2-carbonyl}-amino)-aceticacid: ¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.40 (1H, br s), 10.39 (1H, s),9.37 (1H, t, J=6.1 Hz), 8.43 (1H, d, J=1.9 Hz), 7.97 (1H, s), 7.64-7.71(1H, m), 7.60 (1H, d, J=1.8 Hz), 7.41-7.49 (2H, m), 3.99 (2H, d, J=6.1Hz), 1.73-1.86 (1H, m), 0.74-0.84 (4H, m). HPLC-MS: m/z 356 [M+H]⁺.

({3-Hydroxy-5-[3-(pyrrolidine-1-carbonyl)phenyl]-pyridine-2-carbonyl}amino)-aceticacid: ¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.40 (1H, s), 9.38 (1H, t, J=6.3Hz), 8.55 (1H, d, J=1.8 Hz), 7.88-7.94 (2H, m), 7.77 (1H, d, J=1.8 Hz),7.56-7.63 (2H, m), 4.01 (2H, d, J=6.0 Hz), 3.41-3.54 (4H, m), 1.76-1.96(4H, m). HPLC-MS: m/z 370 [M+H]⁺.

({3-Hydroxy-5-[3-(2H-tetrazol-5-yl)phenyl]-pyridine-2-carbonyl}-amino)-aceticacid: ¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.40 (1H, s), 9.51 (1H, br s),8.50 (1H, s), 8.20 (1H, s), 7.94 (1H, d, J=1.5 Hz), 7.88-7.99 (1H, m),7.72 (1H, d, J=1.9 Hz), 7.34-7.53 (1H, m), 7.48 (2H, d, J=2.2 Hz), 7.00(1H, d, J=1.8 Hz), 6.38 (1H, br s), 3.54 (2H, br s). HPLC-MS: m/z 341[M+H]⁺.

The fourth aspect of Category I of the present disclosure encompassescompounds having the formula:

wherein R units are substituted or unsubstituted heteroaryl.Non-limiting examples of these R units are described in Table IV hereinbelow.

TABLE IV No. R 115 pyridin-2-yl 116 pyridin-3-yl 117 pyridin-4-yl 118pyrimidin-2-yl 119 pyrimidin-4-yl 120 pyrimidin-5-yl 121isoquinolin-1-yl 122 isoquinolin-3-yl 123 isoquinolin-4-yl 124thiazol-2-yl 125 thiazol-4-yl 126 1,2,3,4-tetrazol-5-yl 127[1,2,4]triazol-5-yl 128 imidazol-2-yl 129 furan-2-yl 130 furan-3-yl 131thiophene-2-yl 132 thiophene-3-yl

The compounds which encompass the fourth aspect of Category I of thepresent disclosure can be prepared by the procedure outlined in SchemeII and described in Example 2 herein beginning with compounds which aremembers of the first and second aspect of Category I. The following arenon-limiting examples of compound encompassed by the fourth aspect ofCategory I.

[(5′-Hydroxy-[2,3′]bipyridinyl-6′-carbonyl)-amino]-acetic acid: ¹H NMR(250 MHz, DMSO-d₆) δ ppm 12.45 (1H, s), 9.45 (1H, t, J=6.1 Hz), 8.91(1H, d, J=1.8 Hz), 8.73-8.79 (1H, m) 8.20 (1H, d, J=8.0 Hz), 8.07 (1H,d, J=1.8 Hz), 8.01 (1H, dt, J=7.8, 1.8 Hz), 7.52 (1H, ddd, J=7.5, 4.8,0.9 Hz), 4.01 (2H, d, J=6.1 Hz). HPLC-MS: m/z 274 [M+H]⁺.

[(5-Hydroxy-[3,3′]bipyridinyl-6-carbonyl)-amino]-acetic acid: ¹H NMR(250 MHz, DMSO-d₆) δ ppm 12.44 (1H, br s), 9.46 (1H, t, J=6.1 Hz), 9.30(1H, s), 8.86 (1H, d, J=5.3 Hz), 8.76 (1H, d, J=8.2 Hz), 8.67 (1H, d,J=1.9 Hz), 7.92-8.00 (2H, m), 4.02 (2H, d, J=6.1 Hz). HPLC-MS: m/z 274[M+H]⁺.

[(3-Hydroxy-5-pyrimidin-5-yl-pyridine-2-carbonyl)-amino]-acetic acid: ¹HNMR (250 MHz, DMSO-d₆) δ ppm 12.45 (1H, br s), 9.45 (1H, t, J=5.9 Hz),9.27-9.33 (3H, m), 8.67 (1H, d, J=1.8 Hz), 7.97 (1H, d, J=1.9 Hz), 4.02(2H, d, J=6.2 Hz). HPLC-MS: m/z 275 [M+H]⁺.

[(3-Hydroxy-5-isoquinolin-4-yl-pyridine-2-carbonyl)-aminc]-acetic acid:¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.53 (1H, br s), 9.83 (1H, s), 9.52(1H, t, J=6.1 Hz), 8.71 (1H, s), 8.54 (1H, d, J=8.1 Hz), 8.38 (1H, d,J=1.7 Hz), 7.92-8.13 (3H, m), 7.73 (1H, d, J=1.7 Hz), 4.04 (2H, d, J=6.1Hz). HPLC-MS: m/z 324 [M+H]⁺.

[(3-Hydroxy-5-thiazol-2-yl-pyridine-2-carbonyl)-amino]-acetic acid: ¹HNMR (250 MHz, DMSO-d₆) δ ppm 12.50 (1H, s), 9.46 (1H, t, J=6.1 Hz), 8.76(1H, d, J=1.8 Hz), 8.07 (1H, d, J=3.2 Hz), 8.00 (1H, d, J=3.2 Hz), 7.90(1H, d, J=1.8 Hz), 4.00 (2H, d, J=6.1 Hz). HPLC-MS: m/z 280 [M+H]⁺.

{[5-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid: ¹HNMR (250 MHz, DMSO-d₆) δ ppm 12.83 (1H, br s), 12.32 (1H, s), 9.31 (1H,t, J=6.1 Hz), 8.46 (1H, d, J=1.9 Hz), 7.64 (1H, d, J=1.9 Hz), 7.37 (1H,d, J=2.2 Hz), 7.28-7.34 (1H, m), 6.98 (1H, d, J=8.5 Hz), 4.29 (4H, s),3.99 (2H, d, J=6.1 Hz). HPLC-MS: m/z 331 [M+H]⁺.

Category II of the present disclosure relates to compounds having theformula:

wherein the first aspect encompasses compounds having the formula:

R units are substituted or unsubstituted phenyl. Non-limiting examplesof these R units are described in Table V herein below.

TABLE V No. R 133 2-fluorophenyl 134 3-fluorophenyl 135 4-fluorophenyl136 2-chlorophenyl 137 3-chlorophenyl 138 4-chlorophenyl 1392-cyanophenyl 140 3-cyanophenyl 141 4-cyanophenyl 142 2-methylphenyl 1433-methylphenyl 144 4-methylphenyl 145 2-ethylphenyl 146 3-ethylphenyl147 4-ethylphenyl 148 2-methoxyphenyl 149 3-methoxyphenyl 1504-methoxyphenyl 151 2-ethoxyphenyl 152 3-ethoxyphenyl 153 4-ethoxyphenyl154 2-iso-propoxyphenyl 155 3-iso-propoxyphenyl 156 4-iso-propoxyphenyl157 2-carbamoylphenyl 158 3-carbamoylphenyl 158 4-carbamoylphenyl 1602-(aziridine-1-carbonyl)phenyl 161 3-(aziridine-1-carbonyl)phenyl 1624-(aziridine-1-carbonyl)phenyl 163 2-(azetidine-1-carbonyl)phenyl 1643-(azetidine-1-carbonyl)phenyl 165 4-(azetidine-1-carbonyl)phenyl 1662-(pyrrolidine-1-carbonyl)phenyl 167 3-(pyrrolidine-1-carbonyl)phenyl168 4-(pyrrolidine-1-carbonyl)phenyl 169 2-(piperidine-1-carbonyl)phenyl170 3-(piperidine-1-carbonyl)phenyl 171 4-(piperidine-1-carbonyl)phenyl172 2-(acetylamino)phenyl 173 3-(acetylamino)phenyl 1744-(acetylamino)phenyl 175 2-(ethanecarbonylamino)phenyl 1763-(ethanecarbonylamino)phenyl 177 4-(ethanecarbonylamino)phenyl 1782-(cyclopropanecarbonylamino)phenyl 1793-(cyclopropanecarbonylamino)phenyl 1804-(cyclopropanecarbonylamino)phenyl

The compounds that encompass the first aspect of Category II of thepresent disclosure can be prepared by the procedure outlined in Scheme Vand described in Example 3 herein below.

EXAMPLE 3 [(4′-Chloro-3-methoxy-biphenyl-4-carbonyl)-amino]-acetic acidethyl ester (10)

Preparation of 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid methylester (8): To a degassed solution of methyl 4-bromo-2-methoxybenzoate(0.70 g, 2.86 mmol) in 1,4-dioxane (10 mL) and MeOH (2.5 mL) at roomtemperature under nitrogen blanketing is added 4-chlorophenyl boronicacid (0.536 g, 3.43 mmol), Pd(dppf)Cl₂ (0.233 g, 0.286 mmol) and K₃PO₄(0.728 g, 3.43 mmol). The resulting suspension is heated to 80° C. andstirred for 3 hours after which the reaction is cooled to roomtemperature and filtered through Celite^(TM). The collected solids arewashed with additional MeOH and the filtrate concentrated under reducedpressure. The crude material is purified over silica (hexanes:EtOAcgradient 6:1 to 4:1) to afford 0.614 g (78% yield) of the desiredproduct as orange crystals. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.89 (1H, d,J=8.0 Hz), 7.52-7.56 (2H, m), 7.44 (2H, d, J=8.7 Hz), 7.17 (1H, d, J=8.0Hz), 7.12 (1H, d, J=1.6 Hz), 3.99 (3H, s), 3.92 (3H, s). HPLC-MS: m/z277 [M+H]⁺.

Preparation of 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid (9): To asolution of 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid methyl ester,8, (0.615 g, 2.22 mmol) in THF (20 mL) and H₂O (5 mL) at roomtemperature is added LiOH (0.932 g, 22.2 mmol). The resulting suspensionis heated to reflux for 2 hours. The reaction is cooled and concentratedunder reduced pressure. The crude product is acidified using conc. HCland the resulting solid is collected by filtration washed with H₂O anddried to afford 0.532 g (91%) of the desired product as a grey solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 10.69 (1H, br s), 8.26 (1H, d, J=8.1 Hz),7.53-7.58 (2H, m), 7.44-7.50 (2H, m), 7.33 (1H, dd, J=8.1, 1.6 Hz), 7.20(1H, d, J=1.3 Hz), 4.17 (3H, s). HPLC-MS: m/z 263 [M+H]⁺.

Preparation of [(4′-chloro-3-methoxy-biphenyl-4-carbonyl)-amino]-aceticacid ethyl ester (10): To a solution of4′-chloro-3-methoxy-biphenyl-4-carboxylic acid, 9, (0.325 g, 1.24 mmol)in CH₂Cl₂ (5 mL) and DMF (1.5 mL) at room temperature under N₂ is addedglycine ethyl ester hydrochloride (0.19 g, 1.36 mmol),1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (EDCI) (0.261 g, 1.36mmol), 1-hydroxybenzotriazole (HOBt) (0.033 g, 0.248 mmol) anddiisopropylethylamine (DIPEA) (0.432 ml, 2.28 mmol). The resultingsuspension is stirred for 16 hours after which the reaction mixture isdiluted with EtOAc and washed with 1M HCl, 1M NaOH and saturated aqueousNaCl. The organic phase is separated, dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude material is purified oversilica (hexanes:EtOAc 1:1) to afford 0.364 g (85% yield) of the desiredproduct as a colorless solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.51 (1H, brs), 8.28 (1H, d, J=8.1 Hz), 7.53-7.57 (2H, m), 7.42-7.46 (2H, m), 7.27(1H, dd, J=8.1, 1.6 Hz), 7.14 (1H, d, J=1.5 Hz), 4.29 (2H, d, J=4.8 Hz),4.28 (2H, q, J=7.1 Hz), 4.09 (3H, s), 1.34 (3H, t, J=7.2 Hz). HPLC-MS:m/z 348 [M+H]⁺.

A further non-limiting example includes the following.

[(3-Methoxy-4′-methyl-biphenyl-4-carbonyl)-amino]-acetic acid ethylester: ¹H NMR (400 MHz, CDCl₃) δ ppm 8.52 (br s, 1 H), 8.26 (d, J=8.14Hz, 1 H), 7.53 (d, J=8.05 Hz, 2 H), 7.28-7.33 (m, 3 H), 7.17 (d, J=1.37Hz, 1 H), 4.13-4.45 (m, 4 H), 4.08 (s, 3 H), 2.42 (s, 3 H), 1.33 (t,J=7.18 Hz, 3 H). HPLC-MS: m/z 328 [M+H]⁺.

The compounds of Formula (I) also encompasse compounds having theformula:

wherein R units are substituted or unsubstituted phenyl. Non-limitingexamples of these R units are described in Table VI herein below.

TABLE VI No. R 181 2-fluorophenyl 182 3-fluorophenyl 183 4-fluorophenyl184 2-chlorophenyl 185 3-chlorophenyl 186 4-chlorophenyl 1872-cyanophenyl 188 3-cyanophenyl 189 4-cyanophenyl 190 2-methylphenyl 1913-methylphenyl 182 4-methylphenyl 193 2-ethylphenyl 194 3-ethylphenyl195 4-ethylphenyl 196 2-methoxyphenyl 197 3-methoxyphenyl 1984-methoxyphenyl 199 2-ethoxyphenyl 200 3-ethoxyphenyl 201 4-ethoxyphenyl202 2-iso-propoxyphenyl 203 3-iso-propoxyphenyl 204 4-iso-propoxyphenyl205 2-carbamoylphenyl 206 3-carbamoylphenyl 207 4-carbamoylphenyl 2082-(aziridine-1-carbonyl)phenyl 209 3-(aziridine-1-carbonyl)phenyl 2104-(aziridine-1-carbonyl)phenyl 211 2-(azetidine-1-carbonyl)phenyl 2123-(azetidine-1-carbonyl)phenyl 213 4-(azetidine-1-carbonyl)phenyl 2142-(pyrrolidine-1-carbonyl)phenyl 215 3-(pyrrolidine-1-carbonyl)phenyl216 4-(pyrrolidine-1-carbonyl)phenyl 217 2-(piperidine-1-carbonyl)phenyl218 3-(piperidine-1-carbonyl)phenyl 219 4-(piperidine-1-carbonyl)phenyl220 2-(acetylamino)phenyl 221 3-(acetylamino)phenyl 2224-(acetylamino)phenyl 223 2-(ethanecarbonylamino)phenyl 2243-(ethanecarbonylamino)phenyl 225 4-(ethanecarbonylamino)phenyl 2262-(cyclopropanecarbonylamino)phenyl 2273-(cyclopropanecarbonylamino)phenyl 2284-(cyclopropanecarbonylamino)phenyl

The compounds disclosed immediately above can be prepared by theprocedure outlined in Scheme VI and described in Example 4 herein below.

EXAMPLE 4 [(4′-Chloro-3-hydroxy-biphenyl-4-carbonyl)-amino]-acetic acid(11)

Preparation of [(4′-chloro-3-hydroxy-biphenyl-4-carbonyl)-amino]-aceticacid (11):

To a solution of[(4′-chloro-3-methoxy-biphenyl-4-carbonyl)-amino]-acetic acid ethylester (0.053 g, 0.152 mmol) in CH₂Cl₂ (2 mL) at room temperature undernitrogen is added BBr₃ (1.52 ml of a 1M solution in CH₂Cl₂, 1.52 mmol)dropwise. The resulting mixture is stirred for 3 days after which timethe reaction is quenched with H₂O (0.5 mL) then acidified to pH 1 withconc. HCl. The mixture is extracted with EtOAc (x 2), the organic phaseseparated, dried (MgSO₄), filtered and concentrated under reducedpressure. The crude material is purified by preparative HPLC to afford0.019 g (41% yield) of the desired product as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 12.41 (1H, s), 9.19 (1H, s), 7.96 (1H, d, J=8.3 Hz),7.74 (2H, d, J=8.7 Hz), 7.54 (2H, d, J=8.7 Hz), 7.21 (1H, d, J=1.7 Hz),7.26 (1H, dd, J=8.3, 1.8 Hz), 3.99 (2H, d, J=5.5 Hz). HPLC-MS: m/z 306[M+H]⁺.

The following is a non-limiting example of the second aspect of CategoryII of the present disclosure.

[(3-Hydroxy-4′-methyl-biphenyl-4-carbonyl)-amino]-acetic acid: ¹H NMR(400 MHz, DMSO-d₆) δ ppm 12.37 (1H, s), 9.17 (1H, s), 7.94 (1H, d,J=8.32 Hz), 7.60 (2H, d, J=8.14 Hz), 7.29 (2H, d, J=7.96 Hz), 7.22 (1H,dd, J=8.32, 1.83 Hz), 7.18 (1H, d, J=1.74 Hz), 4.00 (2H, d, J=5.67 Hz),2.35 (3H, s). HPLC-MS: m/z 286 [M+H]⁺.

Category III of the present disclosure relates to compounds having theformula:

wherein non-limiting examples of R, R^(6a) and R^(6b) are furtherdescribed herein below in Table VII.

TABLE VII No. R R^(6a) R^(6b) 229 2-fluorophenyl —H —H 2303-fluorophenyl —H —H 231 4-fluorophenyl —H —H 232 2-chlorophenyl —H —H233 3-chlorophenyl —H —H 234 4-chlorophenyl —H —H 235 2-methylphenyl —H—H 236 3-methylphenyl —H —H 237 4-methylphenyl —H —H 238 2-fluorophenyl—CH₃ —H 239 3-fluorophenyl —CH₃ —H 240 4-fluorophenyl —CH₃ —H 2412-chlorophenyl —CH₃ —H 242 3-chlorophenyl —CH₃ —H 243 4-chlorophenyl—CH₃ —H 244 2-methylphenyl —CH₃ —H 245 3-methylphenyl —CH₃ —H 2464-methylphenyl —CH₃ —H 247 2-fluorophenyl —CH₃ —CH₃ 248 3-fluorophenyl—CH₃ —CH₃ 249 4-fluorophenyl —CH₃ —CH₃ 250 2-chlorophenyl —CH₃ —CH₃ 2513-chlorophenyl —CH₃ —CH₃ 252 4-chlorophenyl —CH₃ —CH₃ 253 2-methylphenyl—CH₃ —CH₃ 254 3-methylphenyl —CH₃ —CH₃ 255 4-methylphenyl —CH₃ —CH₃ 2562-fluorophenyl —CH₂CH₃ —H 257 3-fluorophenyl —CH₂CH₃ —H 2584-fluorophenyl —CH₂CH₃ —H 259 2-chlorophenyl —CH₂CH₃ —H 2603-chlorophenyl —CH₂CH₃ —H 261 4-chlorophenyl —CH₂CH₃ —H 2622-methylphenyl —CH₂CH₃ —H 263 3-methylphenyl —CH₂CH₃ —H 2644-methylphenyl —CH₂CH₃ —H

The compounds which are encompassed within Category III of the presentdisclosure can be prepared by the procedures outlined herein below inSchemes VII and VIII and described in Examples 5 and 6.

EXAMPLE 55-(3-Chlorophenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-ylamide (12)

Preparation of 5-(3-chlorophenyl)-N-(2-dimethylamino-2-oxoethyl)hydroxylpyridin-2-yl amide (12): To a solution of{[5-(3-chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid,7, (0.043 g, 0.139 mmol) in DMF (2 mL) at 0° C. under N₂ is addeddiisopropylethylamine (0.072 ml, 0.42 mmol),1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (EDCI) (0.040 g, 0.21mmol) and 1-hydroxybenzotriazole (HOBt) (0.002 g, 0.014 mmol). Theresulting mixture is stirred for 5 minutes before dimethylamine (0.10 mLof a 2M solution in THF, 0.21 mmol) is added. The reaction is warmedslowly to room temperature and stirred for 3 days. The reaction isdiluted with EtOAc, washed with H₂O, and saturated aqueous NaCl. Theorganic phase is dried (MgSO₄), filtered, concentrated under reducedpressure and the crude material is purified over silica (EtOAc) toafford 0.20 g (43% yield) of the desired product as a colorless solid.¹H NMR (250 MHz, CDCl₃) δ ppm 11.90 (1H, s), 8.83 (1H, t, J=4.6 Hz),8.25 (1H, d, J=1.8 Hz), 7.51 (1H, m), 7.31-7.44 (4H, m), 4.19 (2H, d,J=4.6 Hz), 2.99 (3H, s), 2.98 (3H, s). HPLC-MS: m/z 334 [M+H]⁺.

EXAMPLE 65-(3-Chlorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide(16)

Preparation of 3,5-bis-benzyloxy-N-(2-amino-2-oxoethyl)pyridin-2-ylamide (13): To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylicacid, 2, (1.00 g, 2.99 mmol) in DMF (20 mL) at room temperature under N₂is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.925 g,5.97 mmol) and 1-hydroxybenzotriazole (HOBt) (0.806 g, 5.97 mmol). Theresulting solution is stirred for 15 minutes then 2-aminoacetamidehydrochloride (0.66 g, 5.97 mmol) and diisopropylethylamine (1.56 ml,8.96 mmol) are added. After 3 days the reaction mixture is concentratedunder reduced pressure and H₂O added. The solid which forms is collectedby filtration and is washed with water to afford 0.598 g (51% yield) ofthe desired product as a white solid. ¹H NMR (250 MHz, DMSO-d₆) δ ppm8.39 (1H, t, J=5.6 Hz), 8.01 (1H, d, J=2.2 Hz), 7.28-7.56 (12 H, m),7.11 (1H, br s), 5.26 (2H, s), 5.25 (2H, s), 3.81 (2H, d, J=5.6 Hz).HPLC-MS: m/z 392 [M+H]⁺.

Preparation of 3,5-dihydroxy-N-(2-amino-2-oxoethy)pyridin-2-yl amide(14): A solution of 3,5-bis-benzyloxy-N-(2-amino-2-oxoethyl)pyridin-2-ylamide, 13, (0.598 g, 1.53 mmol) in EtOH (100 mL) containing 10% Pd/C(0.120 g) is stirred under an atmosphere of H₂ for 22 hours. Thereaction solution is filtered through Celite™ and the collected solidsare washed with hot MeOH. The combined filtrate and washings areconcentrated under reduced pressure to afford 0.32 g (99% yield) of thedesired product cream-colored solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.42 (1H, s), 10.84 (1H, br s), 8.75(1H, t, J=5.8 Hz), 7.75 (1H, d, J=2.3 Hz), 7.47 (1H, br s), 7.13 (1H, brs), 6.67 (1H, d, J=2.3 Hz), 3.85 (2H, d, J=5.9 Hz). HPLC-MS: m/z 212[M+H]⁺.

Preparation of5-trifluoromethanesulfonoxy-N-(2-amino-2-oxoethyl)-3-hydroxypyridin-2-ylamide (15): To a solution of3,5-dihydroxy-N-(2-amino-2-oxoethy)pyridin-2-yl amide, 14, (0.30 g, 1.42mmol) in MeOH (10 mL) and DMF (5 mL) at 0° C. under N₂ is addeddiisopropylethylamine (0.247 ml, 1.42 mmol) followed byN-phenyltrifluoromethanesulfonamide (0.508 g, 1.42 mmol). The resultingmixture is warmed slowly to room temperature and stirring is continuedfor 24 hours. The solvent is then removed under reduced pressure and thecrude material is purified over silica (2% MeOH:CH₂Cl₂) to afford 0.404g (83% yield) of the desired product as a pale yellow solid.

¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.85 (1H, br s), 9.28 (1H, t, J=5.9Hz), 8.41 (1H, d, J=2.3 Hz), 7.85 (1H, d, J=2.4 Hz), 7.52 (1H, br s),7.18 (1H, br s), 3.88 (2H, d, J=6.1 Hz). HPLC-MS: m/z 344 [M+H]⁺.

Preparation of5-(3-chlorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxypyridin-2-yl amide(16): To a degassed solution of5-trifluoromethanesulfonoxy-N-(2-amino-2-oxoethyl)-3-hydroxypyridin-2-ylamide, 15, (0.20 g, 0.58 mmol) in 1,4-dioxane (3.5 mL) at roomtemperature under N₂ is added 3-chlorophenyl boronic acid (0.109 g, 0.70mmol), K₃PO₄ (0.148 g, 0.70 mmol) and Pd(dppf)Cl₂ (0.048 g, 0.06 mmol).The resulting suspension is heated to 90° C. in a sealed tube for 22hours. The reaction is cooled to room temperature and additional3-chlorophenyl boronic acid (0.055 g, 0.35 mmol) and Pd(dppf)Cl₂ (0.048g, 0.06 mmol) is added and the reaction reheated to 90° C. for anadditional 22 hours. After cooling, the reaction solution is filteredthrough Celite™ and the collected solids are washed with additionalMeOH. The filtrate and washings are concentrated under reduced pressureand the residue dissolved in CH₂Cl₂ and washed with 10% citric acid. Theorganic layer is dried (Na₂SO₄), filtered and concentrated under reducedpressure. The crude product is purified over silica (2% MeOH:CH₂Cl₂) toafford 0.033 g (18% yield) of the desired product as a colourless solid.¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.46 (1H, s), 9.17 (1H, t, J=5.9 Hz),8.55 (1H, d, J=2.0 Hz), 7.93 (1H, d, J=0.9 Hz), 7.75-7.84 (2H, m),7.49-7.60 (3H, m), 7.18 (1H, s), 3.91 (2H, d, J=5.9 Hz). HPLC-MS: m/z306 [M+H]⁺.

The following are non-limiting examples of compounds encompassed withinCategory III of the present disclosure.

5-(3-Chlorophenyl)-N-(2-is opropylamino-2-oxoethyl)-3-hydroxy-pyridin-2-yl amide: ¹H NMR (250 MHz, CDCl₃) δ ppm 8.60(1H, t, J=6.4 Hz), 8.25 (1H, d, J=2.0 Hz), 7.50-7.53 (1H, m), 7.44 (1H,d, J=2.0 Hz), 7.35-7.43 (3H, m), 5.69 (1H, br s), 4.04 (2H, d, J=5.9Hz), 3.41 (1H, q, J=7.0 Hz), 1.13 (6 H, d, J=6.6 Hz). HPLC-MS: m/z 348[M+H]⁺.

5-(4-Methylphenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxypyridin-2-ylamide:

¹H NMR (250 MHz, CDCl₃) δ ppm 11.90 (1H, s), 8.47 (1H, t, J=5.9 Hz),8.25 (1H, d, J=1.8 Hz), 7.33-7.56 (3H, m), 7.12-7.31 (2H, m), 6.07 (1H,br s), 3.90-4.24 (2H, m), 2.66-2.98 (3H, m), 2.35 (3H, s). HPLC-MS: m/z300 [M+H]⁺.

5-(3-Chlorophenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxy-pyridin-2-ylamide:

¹H NMR (250 MHz, CDCl₃) δ ppm 11.79 (1H, br s), 8.55 (1H, br s), 8.31(1H, s), 7.60 (1H, s), 7.41-7.53 (4H, m), 6.01 (1H, br s), 4.15 (2H, d,J=5.8 Hz), 2.90 (3H, d, J=4.7 Hz). HPLC-MS: m/z 320 [M+H]⁺.

Category IV of the present disclosure relates to compounds having theformula:

wherein the first aspect relates to compounds having the formula:

non-limiting examples of R, R⁵, and L units are further described hereinbelow in Table VIII.

TABLE VIII No. R⁵ R L 265 —H 2-fluorophenyl —C(CH₃)₂— 266 —H3-fluorophenyl —C(CH₃)₂— 267 —H 4-fluorophenyl —C(CH₃)₂— 268 —H2-chlorophenyl —C(CH₃)₂— 269 —H 3-chlorophenyl —C(CH₃)₂— 270 —H4-chlorophenyl —C(CH₃)₂— 271 —H 2-methylphenyl —C(CH₃)₂— 272 —H3-methylphenyl —C(CH₃)₂— 273 —H 4-methylphenyl —C(CH₃)₂— 274 —CH₃2-fluorophenyl —C(CH₃)₂— 275 —CH₃ 3-fluorophenyl —C(CH₃)₂— 276 —CH₃4-fluorophenyl —C(CH₃)₂— 277 —CH₃ 2-chlorophenyl —C(CH₃)₂— 278 —CH₃3-chlorophenyl —C(CH₃)₂— 279 —CH₃ 4-chlorophenyl —C(CH₃)₂— 280 —CH₃2-methylphenyl —C(CH₃)₂— 281 —CH₃ 3-methylphenyl —C(CH₃)₂— 282 —CH₃4-methylphenyl —C(CH₃)₂— 283 —CH₂CH₃ 2-fluorophenyl —C(CH₃)₂— 284—CH₂CH₃ 3-fluorophenyl —C(CH₃)₂— 285 —CH₂CH₃ 4-fluorophenyl —C(CH₃)₂—286 —CH₂CH₃ 2-chlorophenyl —C(CH₃)₂— 287 —CH₂CH₃ 3-chlorophenyl—C(CH₃)₂— 288 —CH₂CH₃ 4-chlorophenyl —C(CH₃)₂— 289 —CH₂CH₃2-methylphenyl —C(CH₃)₂— 290 —CH₂CH₃ 3-methylphenyl —C(CH₃)₂— 291—CH₂CH₃ 4-methylphenyl —C(CH₃)₂— 292 —H 2-fluorophenyl —CH(CH₃)— 293 —H3-fluorophenyl —CH(CH₃)— 294 —H 4-fluorophenyl —CH(CH₃)— 295 —H2-chlorophenyl —CH(CH₃)— 296 —H 3-chlorophenyl —CH(CH₃)— 297 —H4-chlorophenyl —CH(CH₃)— 298 —H 2-methylphenyl —CH(CH₃)— 299 —H3-methylphenyl —CH(CH₃)— 300 —H 4-methylphenyl —CH(CH₃)— 301 —CH₃2-fluorophenyl —CH(CH₃)— 302 —CH₃ 3-fluorophenyl —CH(CH₃)— 303 —CH₃4-fluorophenyl —CH(CH₃)— 304 —CH₃ 2-chlorophenyl —CH(CH₃)— 305 —CH₃3-chlorophenyl —CH(CH₃)— 306 —CH₃ 4-chlorophenyl —CH(CH₃)— 307 —CH₃2-methylphenyl —CH(CH₃)— 308 —CH₃ 3-methylphenyl —CH(CH₃)— 309 —CH₃4-methylphenyl —CH(CH₃)— 310 —CH₂CH₃ 2-fluorophenyl —CH(CH₃)— 311—CH₂CH₃ 3-fluorophenyl —CH(CH₃)— 312 —CH₂CH₃ 4-fluorophenyl —CH(CH₃)—313 —CH₂CH₃ 2-chlorophenyl —CH(CH₃)— 314 —CH₂CH₃ 3-chlorophenyl—CH(CH₃)— 315 —CH₂CH₃ 4-chlorophenyl —CH(CH₃)— 316 —CH₂CH₃2-methylphenyl —CH(CH₃)— 317 —CH₂CH₃ 3-methylphenyl —CH(CH₃)— 318—CH₂CH₃ 4-methylphenyl —CH(CH₃)— 319 —H 2-fluorophenyl —CH₂CH₂— 320 —H3-fluorophenyl —CH₂CH₂— 321 —H 4-fluorophenyl —CH₂CH₂— 322 —H2-chlorophenyl —CH₂CH₂— 323 —H 3-chlorophenyl —CH₂CH₂— 324 —H4-chlorophenyl —CH₂CH₂— 325 —H 2-methylphenyl —CH₂CH₂— 326 —H3-methylphenyl —CH₂CH₂— 327 —H 4-methylphenyl —CH₂CH₂— 328 —CH₃2-fluorophenyl —CH₂CH₂— 329 —CH₃ 3-fluorophenyl —CH₂CH₂— 330 —CH₃4-fluorophenyl —CH₂CH₂— 331 —CH₃ 2-chlorophenyl —CH₂CH₂— 332 —CH₃3-chlorophenyl —CH₂CH₂— 333 —CH₃ 4-chlorophenyl —CH₂CH₂— 334 —CH₃2-methylphenyl —CH₂CH₂— 335 —CH₃ 3-methylphenyl —CH₂CH₂— 336 —CH₃4-methylphenyl —CH₂CH₂— 337 —CH₂CH₃ 2-fluorophenyl —CH₂CH₂— 338 —CH₂CH₃3-fluorophenyl —CH₂CH₂— 339 —CH₂CH₃ 4-fluorophenyl —CH₂CH₂— 340 —CH₂CH₃2-chlorophenyl —CH₂CH₂— 341 —CH₂CH₃ 3-chlorophenyl —CH₂CH₂— 342 —CH₂CH₃4-chlorophenyl —CH₂CH₂— 343 —CH₂CH₃ 2-methylphenyl —CH₂CH₂— 344 —CH₂CH₃3-methylphenyl —CH₂CH₂— 345 —CH₂CH₃ 4-methylphenyl —CH₂CH₂—

The compounds described immediately abover wherein R⁵ is C₁-C₄ linear,branched, or cyclic alkyl can be prepared by the procedures outlinedherein below in Scheme IX and described in Example 7.

EXAMPLE 72-{[5-(3-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionicacid methyl ester (20)

Preparation of2-[(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-2-methyl-propionicacid methyl ester (17): To a solution of3,5-bis-benzyloxy-pyridine-2-carboxylic acid, 2, (1.0 g, 2.99 mmol) inDMF (20 mL) at room temperature under N₂ is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.925 g, 5.97mmol) and 1-hydroxybenzotriazole (HOBt) (0.806 g, 5.97 mmol). Themixture is stirred for 15 minutes after which a-aminoisobutyric acid(0.917 g, 5.97 mmol) and diisopropylethyl-amine (DIPEA) (1.56 mL, 8.96mmol) are added. The resulting solution is stirred at room temperaturefor 16 hours then concentrated under reduced pressure. The resultingbrown oil is purified over silica (EtOAc:heptane 1:1) to afford 0.58 g(45% yield) of the desired compound as a colorless solid. ¹H NMR (250MHz, CDCl₃) δ ppm 8.13 (1H, s), 8.02 (1H, d, J=2.3 Hz), 7.31-7.48 (10 H,m), 6.90 (1H, d, J=2.3 Hz), 5.19 (2H, s), 5.10 (2H, s), 3.74 (3H, s),1.58 (6 H, s). HPLC-MS: m/z 435 [M+H]⁺.

Preparation of2-[(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-2-methyl-propionic acidmethyl ester (18): A solution of2-[(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-2-methylpropionic acidmethyl ester, 17, (0.58 g, 1.34 mmol) in MeOH (100 mL) containing 10%Pd/C (0.116 g) is stirred under an atmosphere of H₂ for 22 hours. Thereaction solution is filtered through Celite^(TM) and the collectedsolids are washed with hot MeOH. The combined filtrate and washings areconcentrated under reduced pressure to afford 0.321 g (94% yield) of thedesired compound as a grey solid. ¹H NMR (250 MHz, MeOD) δ ppm 7.67 (1H,d, J=2.4 Hz), 6.58 (1H, d, J=2.4 Hz), 3.69 (3H, s), 1.56 (6 H, s).HPLC-MS: m/z 255 [M+H]⁺.

Preparation of2-[(3-hydroxy-5-trifluoromethanesulfonyloxy-pyridine-2-carbonyl)-amino]-2-methyl-propionicacid methyl ester (19): To a solution in2-[(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-2-methyl-propionic acidmethyl ester, 18, (0.312 g, 1.23 mmol) in MeOH (10 mL) containingdiisopropylethylamine (0.214 mL, 1.23 mmol) at 0° C. under N₂ is addedN-phenyltrifluoromethanesulfonamide (0.439 g, 1.23 mmol). The reactionis warmed slowly to room temperature and stirred for 40 hours. Thesolvent is removed under reduced pressure and the crude oil whichremains is purified over silica (EtOAc:heptane 1:9) to afford 0.170 g(36% yield) of the desired compound as a yellow oil.

¹H NMR (250 MHz, MeOD) δ ppm 8.85 (1H, br s), 8.19 (1H, d, J=2.4 Hz),7.46 (1H, d, J=2.3 Hz), 3.74 (3H, s), 1.63 (6 H, s). HPLC-MS: m/z 387[M+H]⁺.

Preparation of2-{[5-(3-chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionicacid methyl ester (20): To a degassed solution of 2-[(3-hydroxytrifluoromethanesulfonyloxy-pyridine-2-carbonyl)-amino]-2-methyl-propionicacid methyl ester (0.17 g, 0.44 mmol) in 1,4-dioxane (3 mL) at roomtemperature under N₂ is added 3-chlorophenyl boronic acid (0.082 g, 0.53mmol), K₃PO₄ (0.112 g, 0.53 mmol) and Pd(dppf)Cl₂ (0.036 g, 0.04 mmol).The resulting suspension is heated to 85° C. in a sealed tube for 20hours. After cooling, the reaction solution is filtered through Celite™and the collected solids are washed with additional MeOH. The filtrateand washings are concentrated under reduced pressure and the residuedissolved in CH₂Cl₂ and washed with 10% citric acid. The organic layeris dried (Na₂SO₄), filtered and concentrated under reduced pressure. Thecrude product is purified over silica (EtOAc:heptane 1:4) to afford0.112 g (73% yield) of the desired compound as a colorless oil. ¹H NMR(250 MHz, CDCl₃) δ ppm 11.83 (1H, br s), 8.29 (1H, br s), 8.10 (1H, d,J=2.0 Hz), 7.40 (1H, m), 7.08-7.34 (4H, m), 3.65 (3H, s), 1.55 (6 H, s).HPLC-MS: m/z 349 [M+H]⁺.

The compounds of Formula (I) wherein R⁵ is hydrogen can be prepared bythe procedures outlined herein below in Scheme X and described inExample 8

EXAMPLE 82-{[5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionicacid (21)

Preparation of2-{[5-(3-chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionicacid (21): To a solution of 2-{[5-(3-chlorophenyl)-3-hydroxy-pyridinecarbonyl]-amino}-2-methyl-propionic acid methyl ester, 20, (0.082 g,0.24 mmol) in THF (4 mL) is added LiOH (0.024 g, 0.98 mmol) and H₂O (1mL) and the resulting solution stirred for 3 days at room temperature.The solvent is removed under reduced pressure and the pale yellow solidthat remains is then acidified with 1M HCl to until the pH isapproximately 1 and the solution extracted twice with EtOAc. Thecombined organic layers are combined, dried (Na₂SO₄), filtered andconcentrated under reduced pressure to afford 0.064 g (81% yield) of thedesired compound as a white solid. ¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.99(1H, br s), 12.25 (1H, s), 9.05 (1H, s), 8.53 (1H, d, J=2.0 Hz), 7.91(1H, s), 7.74-7.83 (2H, m), 7.51-7.58 (2H, m), 1.58 (6 H, s). HPLC-MS:m/z 335 [M+H]⁺.

Further non-limiting examples include the following.

3-[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-propionicacid ethyl ester: ¹H NMR (250 MHz, CDCl₃) δ ppm 12.12 (1H, s), 8.44 (1H,t, J=5.9 Hz), 8.31 (1H, d, J=1.8 Hz), 7.44-7.55 (3H, m), 7.30 (2H, d,J=7.9 Hz), 4.21 (2H, q, J=7.2 Hz), 3.76 (2H, q, J=6.4 Hz), 2.68 (2H, t,J=6.2 Hz), 2.43 (3H, s), 1.30 (3H, t, J=7.2 Hz). HPLC-MS: m/z 329[M+H]⁺.

3-[(3-Hydroxy-5-(3-chlorophenyl)-pyridine-2-carbonyl)-amino]-propionicacid ethyl ester: ¹H NMR (400 MHz, CDCl₃) δ ppm 12.16 (1H, s), 8.45 (1H,t, J=5.7 Hz), 8.25 (1H, d, J=1.6 Hz), 7.55 (1H, s), 7.37-7.47 (4H, m),4.20 (2H, q, J=7.1 Hz), 3.75 (2H, q, J=6.3 Hz), 2.68 (2H, t, J=6.2 Hz),1.28 (3H, t, J=7.1 Hz). HPLC-MS: m/z 349 [M+H]⁺.

3-{[5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-propionicacid:

¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.63 (1H, br s), 12.37 (1H, br s), 9.20(1H, t, J=5.6 Hz), 8.50 (1H, d, J=1.8 Hz), 7.91 (1H, s), 7.72-7.84 (2H,m), 7.54 (2H, m), 3.54 (2H, q, J=6.8 Hz), 2.58 (2H, t, J=6.9 Hz).HPLC-MS: m/z 321 [M+H]⁺.

3-[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-propionicacid:

¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.59 (1H, br s), 9.15 (1H, t, J=5.9Hz), 8.46 (1H, d, J=1.8 Hz), 7.70 (2H, d, J=8.2 Hz), 7.66 (1H, d, J=2.0Hz), 7.33 (2H, d, J=8.1 Hz), 3.54 (2H, q, J=6.7 Hz), 2.57 (2H, t, J=7.0Hz), 2.36 (3H, s). HPLC-MS: m/z 301 [M+H]⁺.

2-{[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}-2-methyl-propionicacid: ¹H NMR (250 MHz, DMSO-d₆) δ ppm 12.99 (1H, br s), 12.25 (1H, s),9.05 (1H, s), 8.53 (1H, d, J=2.0 Hz), 7.91 (1H, s), 7.74-7.83 (2H, m),7.51-7.58 (2H, m), 1.58 (6 H, s). HPLC-MS: m/z 335 [M+H]⁺.

The second aspect of Category IV relates to compounds having theformula:

wherein non-limiting examples of R, R^(6a), R^(6b), and L units arefurther described herein below in Table IX.

TABLE IX No. R^(6a) R^(6b) R L 346 —H —H 2-fluorophenyl —C(CH₃)₂— 347 —H—H 3-fluorophenyl —C(CH₃)₂— 348 —H —H 4-fluorophenyl —C(CH₃)₂— 349 —H —H2-chlorophenyl —C(CH₃)₂— 350 —H —H 3-chlorophenyl —C(CH₃)₂— 351 —H —H4-chlorophenyl —C(CH₃)₂— 352 —H —H 2-methylphenyl —C(CH₃)₂— 353 —H —H3-methylphenyl —C(CH₃)₂— 354 —H —H 4-methylphenyl —C(CH₃)₂— 355 —CH₃ —H2-fluorophenyl —C(CH₃)₂— 356 —CH₃ —H 3-fluorophenyl —C(CH₃)₂— 357 —CH₃—H 4-fluorophenyl —C(CH₃)₂— 358 —CH₃ —H 2-chlorophenyl —C(CH₃)₂— 359—CH₃ —H 3-chlorophenyl —C(CH₃)₂— 360 —CH₃ —H 4-chlorophenyl —C(CH₃)₂—361 —CH₃ —H 2-methylphenyl —C(CH₃)₂— 362 —CH₃ —H 3-methylphenyl—C(CH₃)₂— 363 —CH₃ —H 4-methylphenyl —C(CH₃)₂— 364 —CH₃ —CH₃2-fluorophenyl —C(CH₃)₂— 365 —CH₃ —CH₃ 3-fluorophenyl —C(CH₃)₂— 366 —CH₃—CH₃ 4-fluorophenyl —C(CH₃)₂— 367 —CH₃ —CH₃ 2-chlorophenyl —C(CH₃)₂— 368—CH₃ —CH₃ 3-chlorophenyl —C(CH₃)₂— 369 —CH₃ —CH₃ 4-chlorophenyl—C(CH₃)₂— 370 —CH₃ —CH₃ 2-methylphenyl —C(CH₃)₂— 371 —CH₃ —CH₃3-methylphenyl —C(CH₃)₂— 372 —CH₃ —CH₃ 4-methylphenyl —C(CH₃)₂— 373—CH₂CH₃ —H 2-fluorophenyl —CH(CH₃)— 374 —CH₂CH₃ —H 3-fluorophenyl—CH(CH₃)— 375 —CH₂CH₃ —H 4-fluorophenyl —CH(CH₃)— 376 —CH₂CH₃ —H2-chlorophenyl —CH(CH₃)— 377 —CH₂CH₃ —H 3-chlorophenyl —CH(CH₃)— 378—CH₂CH₃ —H 4-chlorophenyl —CH(CH₃)— 379 —CH₂CH₃ —H 2-methylphenyl—CH(CH₃)— 380 —CH₂CH₃ —H 3-methylphenyl —CH(CH₃)— 381 —CH₂CH₃ —H4-methylphenyl —CH(CH₃)— 382 —CH₂CH₃ —CH₂CH₃ 2-fluorophenyl —CH(CH₃)—383 —CH₂CH₃ —CH₂CH₃ 3-fluorophenyl —CH(CH₃)— 384 —CH₂CH₃ —CH₂CH₃4-fluorophenyl —CH(CH₃)— 385 —CH₂CH₃ —CH₂CH₃ 2-chlorophenyl —CH(CH₃)—386 —CH₂CH₃ —CH₂CH₃ 3-chlorophenyl —CH(CH₃)— 387 —CH₂CH₃ —CH₂CH₃4-chlorophenyl —CH(CH₃)— 388 —CH₂CH₃ —CH₂CH₃ 2-methylphenyl —CH(CH₃)—389 —CH₂CH₃ —CH₂CH₃ 3-methylphenyl —CH(CH₃)— 390 —CH₂CH₃ —CH₂CH₃4-methylphenyl —CH(CH₃)—

Another subgenus of the Compounds of Formula (I) can be prepared by theprocedures outlined herein below in Scheme XI and described in Example9.

EXAMPLE 95-(3-Chlorophenyl)-N-(2-methylamino2-oxo-1,1-dimethyethyl)-3-hydroxy-pyridin-2-ylamide (22)

Preparation of5-(3-chlorophenyl)-N-(2-methylamino2-oxo-1,1-dimethyethyl)hydroxy-pyridin-2-yl amide (22): To a solution of2-{[5-(3-chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionicacid, 21, (0.030 g, 0.09 mmol) in DMF (2 mL) at room temperature underN₂ is added 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide (EDCI)(0.021 g, 0.13 mmol), 1-hydroxybenzotriazole (HOBt) (0.012 g, 0.09 mmol)and diisopropylethylamine (DIPEA) (0.047 ml, 0.27 mmol). The reaction isstirred for 5 minutes then methylamine hydrochloride (0.09 g, 0.13 mmol)is added. After stirring for 2 days, the solvent is removed underreduced pressure and the residue partitioned between CH₂Cl₂ and H₂O. Theorganic layer is separated, washed with sat. NaCl, dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude product ispurified over silica (MeOH:CH₂Cl₂ 1:99) to afford 0.025 g (80% yield) ofthe desired compound as a colorless oil. ¹H NMR (250 MHz, CDCl₃) δ ppm11.93 (1H, br s), 8.50 (1H, s), 8.26 (1H, d, J=1.8 Hz), 7.56 (1H, d,J=1.4 Hz), 7.38-7.50 (4H, m), 6.50 (1H, br s), 2.87 (3H, d, J=4.7 Hz),1.71 (6 H, s). HPLC-MS: m/z 348 [M+H]⁺.

Another subgenus of the compounds of Formula (I) relates to compoundshaving the formula:

which can be exemplified by compounds having the formula:

wherein the R¹ units are substituted or unsubstituted phenyl.Non-limiting examples of these units are described in Table X hereinbelow.

TABLE X No. R¹ 391 2-fluorophenyl 392 3-fluorophenyl 393 4-fluorophenyl394 2-chlorophenyl 395 3-chlorophenyl 396 4-chlorophenyl 3972-cyanophenyl 398 3-cyanophenyl 399 4-cyanophenyl 400 2-methylphenyl 4013-methylphenyl 402 4-methylphenyl 403 2-ethylphenyl 404 3-ethylphenyl405 4-ethylphenyl 406 2-methoxyphenyl 407 3-methoxyphenyl 4084-methoxyphenyl 409 2-ethoxyphenyl 410 3-ethoxyphenyl 411 4-ethoxyphenyl412 2-iso-propoxyphenyl 413 3-iso-propoxyphenyl 414 4-iso-propoxyphenyl415 2-carbamoylphenyl 416 3-carbamoylphenyl 417 4-carbamoylphenyl 4182-(aziridine-1-carbonyl)phenyl 419 3-(aziridine-1-carbonyl)phenyl 4204-(aziridine-1-carbonyl)phenyl 421 2-(azetidine-1-carbonyl)phenyl 4223-(azetidine-1-carbonyl)phenyl 423 4-(azetidine-1-carbony l)phenyl 4242-(pyrrolidine-1-carbonyl)phenyl 425 3-(pyrrolidine-1-carbonyl)phenyl426 4-(pyrrolidine-1-carbonyl)phenyl 427 2-(piperidine-1-carbonyl)phenyl428 3-(piperidine-1-carbonyl)phenyl 429 4-(piperidine-1-carbonyl)phenyl430 2-(acetylamino)phenyl 431 3-(acetylamino)phenyl 4324-(acetylamino)phenyl 433 2-(ethanecarbonylamino)phenyl 4343-(ethanecarbonylamino)phenyl 435 4-(ethanecarbonylamino)phenyl 4362-(cyclopropanecarbonylamino)phenyl 4373-(cyclopropanecarbonylamino)phenyl 4384-(cyclopropanecarbonylamino)phenyl

Another subgenus of the compounds of Formula (I) can be prepared by theprocedure outlined in Scheme XII and described in Example 10 hereinbelow.

EXAMPLE 10 [(4-(4-Methylphenyl)pyridine-2-carbonyl)amino]-acetic acidmethyl ester (24)

Preparation of [(4-iodo-pyridine-2-carbonyl)-amino]-acetic acid methylester (23): To a solution of 4-iodo-picolinic acid (1.41 g, 5.66 mmol)in CH₂Cl₂ (35 mL) at room temperature under N₂ is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.62 g, 8.49 mmol)and 1-hydroxybenzotriazole (HOBt) (0.077 g, 0.57 mmol). The solution isstirred for 5 minutes and glycine methyl ester hydrochloride (1.07 g,8.49 mmol) is added and the reaction is stirred 16 hours. The reactionvolume is concentrated under reduced pressure and the crude material waspartitioned between EtOAc and 1M K₂CO₃. The aqueous phase is removed andthe organic phase washed with H₂O, sat. NaCl, dried (MgSO₄), filteredand concentrated under reduced pressure to afford a brown oil which ispurified over silica (EtOAc:heptane gradient 1:4) to afford 0.805 g (44%yield) of the desired product as a colorless solid. HPLC-MS: m/z 321[M+H]⁺.

Preparation of [(4-(4-methylphenyl)pyridine-2-carbonyl)amino]-aceticacid methyl ester (24): To a degassed solution of[(4-iodo-pyridine-2-carbonyl)-amino]-acetic acid methyl ester, 23,(0.150, 0.47 mmol) in 1,4-dioxane (4 mL) and MeOH (2 mL) is added K₃PO₄(0.109 mg, 0.52 mmol), Pd(dppf)Cl₂ (0.038 g, 0.047 mmol) and4-methylphenyl boronic acid (0.064 g, 0.47 mmol). The reaction is heatedto 70° C. in a sealed tube under N₂ for 16 hours. The solvents are thenremoved under reduced pressure and the solid which remains ispartitioned between CH₂Cl₂ and 1M K₂CO₃. The aqueous phase is removedand the organic phase washed with H₂O, sat. NaCl, dried (MgSO₄),filtered and concentrated under reduced pressure. The crude material ispurified over silica (EtOAc:heptane gradient 1:4 to 3:7) to afford 0.113g (85% yield) of the desired compound. ¹H NMR (400 MHz, CDCl₃) δ ppm8.60 (1H, dd, J=5.1, 0.7 Hz), 8.55 (1H, t, J=4.8 Hz), 8.43-8.44 (1H, m),8.43 (1H, s), 7.66 (1H, dd, J=5.1, 1.8 Hz), 7.63 (2H, d, J=8.4 Hz), 7.32(2H, d, J=8.1 Hz), 4.31 (1H, d, J=5.9 Hz), 3.81 (2H, s), 2.43 (3H, s).HPLC-MS: m/z 285 [M+H]⁺.

The following are non-limiting examples of compounds describedimmediately above.

{[4-(4-Cyanophenyl)pyridine-2-carbonyl]amino}-acetic acid methyl ester:¹H NMR (400 MHz, CDCl₃) δ ppm 8.63 (1H, d, J=5.1 Hz), 8.45 (1H, t, J=5.3Hz), 8.36 (1H, d, J=1.8 Hz), 7.74 (4H, s), 7.59 (1H, dd, J=5.1, 1.8 Hz),4.24 (2H, d, J=5.9 Hz), 3.74 (3H, s). HPLC-MS: m/z 296 [M+H]⁺.

{[4-(4-Chlorophenyl)pyridine-2-carbonyl]amino}-acetic acid methyl ester:¹H NMR (400 MHz, CDCl₃) δ ppm 8.56 (1H, dd, J=4.9, 0.9 Hz), 8.47 (1H, t,J=5.1 Hz), 8.33 (1H, dd, J=2.0, 0.9 Hz), 7.51-7.61 (3H, m), 7.41 (2H,m), 4.23 (2H, d, J=5.5 Hz), 3.74 (3H, s). HPLC-MS: m/z 305 [M+H]⁺.

{[4-(3-Chlorophenyl)pyridine-2-carbonyl]amino}acetic acid methyl ester:¹H NMR (400 MHz, CDCl₃) δ ppm 8.57 (1H, dd, J=5.1, 0.7 Hz), 8.47 (1H, t,J=5.1 Hz), 8.33 (1H, m), 7.62 (1H, m), 7.57 (1H, dd, J=5.1, 1.8 Hz),7.47-7.54 (1H, m), 7.31-7.42 (2H, m), 4.24 (2H, d, J=5.9 Hz), 3.74 (3H,s). HPLC-MS: m/z 305 [M+H]⁺.

{[4-(2-Chlorophenyl)pyridine-2-carbonyl]-amino}-acetic acid methylester: ¹H NMR (400 MHz, CDCl₃) δ ppm 8.57 (1H, dd, J=5.1, 0.7 Hz), 8.46(1H, t, J=4.6 Hz), 8.20 (1H, dd, J=1.8, 0.7 Hz), 7.50 (1H, dd, J=5.1,1.8 Hz), 7.42-7.46 (1H, m), 7.30 (1H, d, J=1.8 Hz), 7.28-7.32 (2H, m),4.23 (2H, d, J=5.5 Hz), 3.74 (3H, s). HPLC-MS: m/z 305 [M+H]⁺.

The second aspect of Category V encompasses compounds having theformula:

wherein R¹ units are substituted or unsubstituted phenyl, non-limitingexamples of which are described in Table XI herein below.

TABLE XI No. R¹ 439 2-fluorophenyl 440 3-fluorophenyl 441 4-fluorophenyl442 2-chlorophenyl 443 3-chlorophenyl 444 4-chlorophenyl 4452-cyanophenyl 446 3-cyanophenyl 447 4-cyanophenyl 448 2-methylphenyl 4493-methylphenyl 450 4-methylphenyl 451 2-ethylphenyl 452 3-ethylphenyl453 4-ethylphenyl 454 2-methoxyphenyl 455 3-methoxyphenyl 4564-methoxyphenyl 457 2-ethoxyphenyl 458 3-ethoxyphenyl 459 4-ethoxyphenyl460 2-iso-propoxyphenyl 461 3-iso-propoxyphenyl 462 4-iso-propoxyphenyl463 2-carbamoylphenyl 464 3-carbamoylphenyl 465 4-carbamoylphenyl 4662-(aziridine-1-carbonyl)phenyl 467 3-(aziridine-1-carbonyl)phenyl 4684-(aziridine-1-carbonyl)phenyl 469 2-(azetidine-1-carbonyl)phenyl 4703-(azetidine-1-carbonyl)phenyl 471 4-(azetidine-1-carbonyl)phenyl 4722-(pyrrolidine-1-carbonyl)phenyl 473 3-(pyrrolidine-1-carbonyl)phenyl474 4-(pyrrolidine-1-carbonyl)phenyl 475 2-(piperidine-1-carbonyl)phenyl476 3-(piperidine-1-carbonyl)phenyl 477 4-(piperidine-1-carbonyl)phenyl478 2-(acetylamino)phenyl 479 3-(acetylamino)phenyl 4804-(acetylamino)phenyl 481 2-(ethanecarbonylamino)phenyl 4823-(ethanecarbonylamino)phenyl 483 4-(ethanecarbonylamino)phenyl 4842-(cyclopropanecarbonylamino)phenyl 4853-(cyclopropanecarbonylamino)phenyl 4864-(cyclopropanecarbonylamino)phenyl

The compounds of the second aspect can be prepared by the procedureoutlined in Scheme XIII and described in Example 11 herein below.

EXAMPLE 11 [(4-(4-Methyl-phenyl)pyridine-2-carbonyl)-amino]-acetic acid(25)

Preparation of [(4-(4-Methyl-phenyl)pyridine-2-carbonyl)-amino]-aceticacid (25): To a solution of[(4-(4-methyl-phenyl)pyridine-2-carbonyl)-amino]-acetic acid methylester, 24, (0.092 g, 0.32 mmol) in THF (2 mL) at room temperature isadded H₂O (1 mL) and LiOH·H₂O (0.027 g, 0.64 mmol). The reaction isstirred for 16 hours after which time the solution is acidified using 1MHCl. The solvents are removed under reduced pressure and the solid thatremains is suspended in a mixture of THF: MeOH and filtered. Thefiltrate is concentrated under reduced pressure and the resulting solidis triturated with MeOH and collected by filtration to provide 0.012 g(12% yield) of the desired compound as a colorless solid. ¹H NMR (250MHz, MeOD) δ ppm 8.69 (1H, d, J=4.8 Hz), 8.38 (1H, s), 7.86 (1H, d,J=6.2 Hz), 7.72 (2H, d, J=8.1 Hz), 7.38 (1H, d, J=7.9 Hz), 4.21 (1H, s),2.44 (2H, s). HPLC-MS: m/z 271 [M+H]⁺.

The following are non-limiting examples of compounds compounds ofFormula (I).

{[4-(4-Cyanophenyl)pyridine-2-carbonyl]amino}-acetic acid: ¹H NMR (250MHz, MeOD) δ ppm 8.69 (1H, d, J=6.0 Hz), 8.38 (1H, br s), 7.71-8.01 (2H,m), 4.10 (2H, s). HPLC-MS: m/z 282 [M+H]⁺.

{[4-(4-Chlorophenyl)pyridine-2-carbonyl]-amino}-acetic acid: ¹H NMR (250MHz, MeOD) δ ppm 8.75 (1H, s), 8.44 (1H, br s), 7.85 (3H, m), 7.57 (2H,d, J=7.8 Hz), 4.23 (2H, s). HPLC-MS: m/z 291 [M+H]⁺.

{[4-(3-Chlorophenyl)pyridine-2-carbonyl]amino}-acetic acid: ¹H NMR (400MHz, MeOD) δ ppm 8.63 (1H, d, J=5.5 Hz), 8.27 (1H, br s), 7.73 (1H, s),7.77 (1H, d, J=4.0 Hz), 7.64 (1H, d, J=7.0 Hz), 7.36-7.49 (3H, m), 4.09(2H, s). HPLC-MS: m/z 291 [M+H]⁺.

{[4-(2-Chlorophenyl)pyridine-2-carbonyl]amino}-acetic acid: ¹H NMR (250MHz, MeOD) δ ppm 8.63 (1H, d, J=4.9 Hz), 8.05-8.10 (1H, m), 7.55 (1H,dd, J=4.9, 1.6 Hz), 7.46 (1H, dt, J=3.9, 2.1 Hz), 7.35 (4H, d, J=2.7Hz), 4.08 (2H, s). HPLC-MS: m/z 291 [M+H]⁺.

Another subgenus of the compounds of Formula (I) have the formula:

wherein non-limiting examples of R and R⁶ are further described hereinbelow in Table XII.

TABLE XII No. R R⁶ 487 —H —H 488 —H —CH₃ 489 —H —CH₂CH₃ 490 —H—CH₂CH₂CH₃ 491 —H —C(CH₃)₃ 492 —OH —H 493 —OH —CH₃ 494 —OH —CH₂CH₃ 495—OH —CH₂CH₂CH₃ 496 —OH —C(CH₃)₃ 497 —Cl —H 498 —Cl —CH₃ 499 —Cl —CH₂CH₃500 —Cl —CH₂CH₂CH₃ 501 —Cl —C(CH₃)₃ 502 —OCH₃ —H 503 —OCH₃ —CH₃ 504—OCH₃ —CH₂CH₃ 505 —OCH₃ —CH₂CH₂CH₃ 506 —OCH₃ —C(CH₃)₃ 507 —CN —H 508 —CN—CH₃ 509 —CN —CH₂CH₃ 510 —CN —CH₂CH₂CH₃ 511 —CN —C(CH₃)₃ 512 —F —H 513—F —CH₃ 514 —F —CH₂CH₃ 515 —F —CH₂CH₂CH₃ 516 —F —C(CH₃)₃

The compounds described above can be prepared by the procedures outlinedin Schemes XIV-XVI and described in Examples 12-14 herein below.

EXAMPLE 12 [(3,5-Dihydroxy-pyridine-2-carbonyl)-amino]-acetic acidtert-butyl ester (27)

Preparation of [(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-aceticacid tert-butyl ester (26): To a solution of3,5-bis-benzyloxy-pyridine-2-carboxylic acid, 2, (2.36 g, 6.36 mmol) inDMF (20 mL) at room temperature under N₂ is added1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (EDCI) (1.83 g, 9.54mmol) and 1-hydroxybenzo-triazole (HOBt) (0.086 g, 0.64 mmol). Themixture is stirred for 15 minutes after which time glycine tert-butylester hydrochloride (1.60 g, 9.54 mmol) and diisopropylethylamine(DIPEA) (3.32 ml, 19.08 mmol) are added. The resulting solution isstirred at room temperature for 48 hours then concentrated under reducedpressure. The resulting brown oil is purified over silica (EtOAc) toafford 3.04 g (99% yield) of the desired compound as a yellow solid. ¹HNMR (250 MHz, CDCl₃) δ ppm 8.19 (1H, t, J=5.2 Hz), 8.01-8.08 (2H, m),7.27-7.54 (9 H, m), 6.97 (1H, d, J=2.4 Hz), 5.24 (2H, s), 5.13 (2H, s),4.17 (2H, d, J=5.2 Hz), 1.51 (9 H, s). HPLC-MS: m/z 449 [M+H]⁺.

Preparation of [(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-acetic acidtert-butyl ester (27): A solution of[(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-acetic acid tert-butylester, 26, (3.04 g, 6.79 mmol) in EtOH (100 mL) containing 10% Pd/C(0.300 g) is stirred under an atmosphere of H₂ for 22 hours. Thesuspension is then filtered through Celite™, concentrated under reducedpressure, and the crude product purified over silica (2.5% MeOH/CH₂Cl₂)to afford 1.20 g (66% yield) of the desired compound as a colorless oil.¹H NMR (250 MHz, CDCl₃) δ ppm 11.90 (1H, br s), 8.94 (1H, br s), 8.20(1H, t, J=5.6 Hz), 7.76 (1H, d, J=2.4 Hz), 6.77 (1H, d, J=2.1 Hz), 4.13(2H, d, J=5.5 Hz), 1.53 (9 H, s). HPLC-MS: m/z 269 [M+H]⁺.

EXAMPLE 13 [(3,5-Dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid (29)

Preparation of [(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid(29): To a solution of[(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid tert-butylester, 28, (0.10 g, 0.37 mmol) in CH₂Cl₂ (4 mL) at room temperature isadded trifluoroacetic acid (1 mL). The reaction is stirred for 16 hoursat room temperature and then concentrated under reduced pressure. Thesolid that remains is collected by filtration, washed with Et₂O toafford 0.070 g (89% yield) of the desired compound as a colorless solid.¹H NMR (250 MHz, DMSO-d₆) δ ppm 10.86 (1H, br s), 9.00 (1H, t, J=6.1Hz), 7.77 (1H, d, J=2.4 Hz), 6.69 (1H, d, J=2.4 Hz), 3.95 (1H, d, J=6.2Hz). HPLC-MS: m/z 213 [M+H]⁺.

EXAMPLE 14 [(3-Hydroxy-pyridine-2-carbonyl)-amino]-acetic acid (30)

Preparation of [(3-hydroxy-pyridine-2-carbonyl)-amino]-acetic acidtert-butyl ester (29): To a solution of 3-hydroxypicolinic acid (0.20 g,1.44 mmol) in DMF (5 mL) at 0° C. under N₂ is addeddiisopropylethylamine (DIPEA) (0.75 ml, 4.3 mmol),1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (EDCI) (0.412 g, 2.9mmol) and 1-hydroxybenzo-triazole (HOBt) (0.019 g, 0.14 mmol). Theresulting mixture is stirred for 5 min before glycine tert-butyl esterHCl (0.36 g, 2.9 mmol) is introduced. The resulting solution is stirredat room temperature for 3 days then concentrated under reduced pressure.The reaction mixture is diluted with EtOAc then washed with 1M HCl, sat.NaCl, and the organic layer is dried (MgSO₄), filtered and concentratedunder reduced pressure to a crude oil that is purified over silica(EtOAc/heptane 1:4) to afford 0.078 g (22% yield) of the desiredcompound as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 11.80 (1H,s), 8.39 (1H, br s), 8.02 (1H, dd, J=4.4, 1.5 Hz), 7.27 (1H, dd, J=8.8,4.4 Hz), 7.25 (1H, dd, J=8.4, 1.5 Hz), 4.06 (2H, d, J=5.5 Hz), 1.44 (9H, s). HPLC-MS: m/z 197 [M-tBu]⁺.

Preparation of [(3-Hydroxy-pyridine-2-carbonyl)-amino]-acetic acid (30):To a solution of [(3-hydroxy-pyridine-2-carbonyl)-amino]-acetic acidtert-butyl ester, 29, (0.070 g, 0.277 mmol) in CH₂Cl₂ (4 mL) is addedTFA (1 mL). The resulting solution is stirred for 5 hours thenconcentrated under reduced pressure to afford 0.054 g (99% yield) of thedesired compound as a colorless solid. ¹H NMR (400 MHz, MeOD) δ ppm 8.09(1H, d, J=3.3 Hz), 7.36-7.59 (2H, m), 4.08 (2H, s). HPLC-MS: m/z 197[M+H]⁺.

Category VII of the present disclosure relates to compounds having theformula:

wherein non-limiting examples of R and R⁶ are further described hereinbelow in Table XIII.

TABLE XIII No. R R⁶ 517 3-fluorophenyl —H 518 4-fluorophenyl —H 5193-chlorophenyl —H 520 4-chlorophenyl —H 521 3-cyanophenyl —H 5224-cyanophenyl —H 523 3-methylphenyl —H 524 4-methylphenyl —H 5253-ethylphenyl —H 526 4-ethylphenyl —H 527 3-methoxyphenyl —H 5284-methoxyphenyl —H 529 3-ethoxyphenyl —H 530 4-ethoxyphenyl —H 5313-fluorophenyl —CH₃ 532 4-fluorophenyl —CH₃ 533 3-chlorophenyl —CH₃ 5344-chlorophenyl —CH₃ 535 3-cyanophenyl —CH₃ 536 4-cyanophenyl —CH₃ 5373-methylphenyl —CH₃CH₃ 538 4-methylphenyl —CH₃ 539 3-ethylphenyl —CH₃540 4-ethylphenyl —CH₃ 541 3-methoxyphenyl —CH₃ 542 4-methoxyphenyl —CH₃543 3-ethoxyphenyl —CH₃ 544 4-ethoxyphenyl —CH₃ 545 3-fluorophenyl—CH₂CH₃ 546 4-fluorophenyl —CH₂CH₃ 547 3-chlorophenyl —CH₂CH₃ 5484-chlorophenyl —CH₂CH₃ 549 3-cyanophenyl —CH₂CH₃ 550 4-cyanophenyl—CH₂CH₃ 551 3-methylphenyl —CH₂CH₃ 552 4-methylphenyl —CH₂CH₃ 5533-ethylphenyl —CH₂CH₃ 554 4-ethylphenyl —CH₂CH₃ 555 3-methoxyphenyl—CH₂CH₃ 556 4-methoxyphenyl —CH₂CH₃ 557 3-ethoxyphenyl —CH₂CH₃ 5584-ethoxyphenyl —CH₂CH₃

The compounds which encompass Category VII of the present disclosure canbe prepared by the procedures outlined in Schemes XVII and XVIII anddescribed in Examples 15 and 16 herein below.

EXAMPLE 15 3-Methoxy-4′-methyl-biphenyl-4-carboxylic acid methyl ester(30)

Preparation of 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid methylester (28): To a degassed solution of methyl 4-bromo-2-methoxybenzoate(0.70 g, 2.86 mmol) in 1,4-dioxane (10 mL) and MeOH (2.5 mL) is added4-chlorophenyl boronic acid (0.536 g, 3.43 mmol), Pd(dppf)Cl₂ (0.233 g,0.286 mmol) and K₃PO₄ (0.728 g, 3.43 mmol). The resulting suspension isheated to 80° C. and stirred for 3 hours. After this time, the reactionis cooled to room temperature and filtered through Celite™. The solidsthat form are collected and washed with additional MeOH before thefiltrate is concentrated under reduced pressure. The crude material ispurified over silica (hexanes:EtOAc; 6:1 to 4:1) to provide 0.615 g (78%yield) of the desired compound as orange crystals. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.89 (1H, d, J=8.0 Hz), 7.52-7.56 (2H, m), 7.44 (2H, d,J=8.7 Hz), 7.17 (1H, d, J=8.0 Hz), 7.12 (1H, d, J=1.6 Hz), 3.99 (3H, s),3.92 (3H, s). HPLC-MS: m/z 277 [M+H]⁺.

EXAMPLE 16 4′-Chloro-3-methoxy-biphenyl-4-carboxylic acid

Preparation of 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid (31): To asolution of 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid methyl ester,30, (0.615 g, 2.22 mmol) in THF (20 mL) and H₂O (5 mL) is added LiOH(0.932 g, 22.2 mmol). The resulting suspension is heated to reflux for 2hours. The reaction is cooled and concentrated under reduced pressure.The crude product is acidified using conc. HCl and the resulting solidis collected by filtration, washed with H₂O to afford 0.532 g (91%yield) of the desired compound as a grey solid. ¹H NMR (400 MHz, CDCl₃)δ ppm 10.69 (1H, br s), 8.26 (1H, d, J=8.1 Hz), 7.53 — 7.58 (2H, m),7.44 — 7.50 (2H, m), 7.33 (1H, dd, J=8.1, 1.6 Hz), 7.20 (1H, d, J=1.3Hz), 4.17 (3H, s). HPLC-MS: m/z 263 [M+H]⁺.

The following are non-limiting examples of additional compounds ofFormula (I)..

3-Methoxy-4′-methyl-biphenyl-4-carboxylic acid methyl ester: ¹H NMR (250MHz, CDCl₃) δ ppm 7.89 (1H, d, J=7.9 Hz), 7.52 (2H, d, J=8.2 Hz),7.25-7.32 (2H, m), 7.15-7.24 (2H, m), 3.99 (3H, s), 3.92 (3H, s), 2.42(3H, s). HPLC-MS: m/z 257 [M+H]⁺.

3-Methoxy-4′-methyl-biphenyl-4-carboxylic acid: ¹H NMR (400 MHz, CDCl₃)δ ppm 10.74 (1H, br s), 8.24 (1H, d, J=8.1 Hz), 7.52 (2H, d, J=8.1 Hz),7.36 (1H, dd, J=8.1, 1.5 Hz), 7.30 (2H, d, J=7.9 Hz), 7.23 (1H, d, J=1.4Hz), 4.16 (3H, s), 2.43 (3H, s). HPLC-MS: m/z 243 [M+H]⁺.

Additional compounds of Formula (I) the formula:

wherein non-limiting examples of R^(8a), R^(8b), R⁹ and R⁶ are furtherdescribed herein below in Table.

TABLE XIV No. R R⁶ R^(8a) R^(8b) R⁹ 559 3-chlorophenyl —H —CH₃ —H —H 5603-chlorophenyl —CH₃ —CH₃ —H —H 561 3-chlorophenyl —H —CH₃ —CH₃ —H 5623-chlorophenyl —CH₃ —CH₃ —CH₃ —H 563 3-chlorophenyl —H —CH₃ —CH₃ —CH₃564 3-chlorophenyl —CH₃ —CH₃ —CH₃ —CH₃ 565 4-chlorophenyl —H —CH₃ —H —H566 4-chlorophenyl —CH₃ —CH₃ —H —H 567 4-chlorophenyl —H —CH₃ —CH₃ —H568 4-chlorophenyl —CH₃ —CH₃ —CH₃ —H 569 4-chlorophenyl —H —CH₃ —CH₃—CH₃ 570 4-chlorophenyl —CH₃ —CH₃ —CH₃ —CH₃ 571 4-methylphenyl —H —CH₃—H —H 572 4-methylphenyl —CH₃ —CH₃ —H —H 573 4-methylphenyl —H —CH₃ —CH₃—H 574 4-methylphenyl —CH₃ —CH₃ —CH₃ —H 575 4-methylphenyl —H —CH₃ —CH₃—CH₃ 576 4-methylphenyl —CH₃ —CH₃ —CH₃ —CH₃

The compounds described above can be prepared by the procedures outlinedherein below in Schemes XIX and XX and described in Examples 17 and 18herein below.

EXAMPLE 17 [(3-Hydroxy-pyridine-2-carbonyl)-methyl-amino]-acetic acidethyl ester (32)

Preparation of [(3-hydroxy-pyridine-2-carbonyl)methylamino]acetic acidethyl ester (31): To a solution of 3-hydroxy picolinic acid (0.40 g,2.88 mmol) in DMF (5 mL) is added diisopropylethylamine (DIPEA) (1.50ml, 8.63 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (EDCI)(0.825 g, 4.31 mmol) and 1-hydroxybenzotriazole (HOBt) (0.039 g, 0.29mmol). The reaction mixture is stirred for 5 minutes thenmethylamino-acetic acid ester hydrochloride (0.663 g, 4.31 mmol) isadded. The reaction is stirred at room temperature for 32 hours afterwhich the solvent is removed under reduced pressure.

The residue is partitioned between EtOAc and 1M HCl and the organiclayer separated, dried (MgSO₄), filtered and concentrated under reducedpressure. The crude material is purified over silica (EtOAc:hexanes 1:1)to afford 0.10 g (15% yield) of the desired compound as a colourlesssolid. HPLC-MS: m/z 240 [M+H]⁺.

EXAMPLE 18 [(3-Hydroxy-pyridine-2-carbonyl)-methyl-amino]-acetic acid(33)

Preparation of [(3-hydroxy-pyridine-2-carbonyl)-methyl-amino]-aceticacid (33): To a solution of[(3-hydroxy-pyridine-2-carbonyl)methylamino]acetic acid ethyl ester, 32,(0.10 g, 0.42 mmol) in THF (4 mL) is added H₂O (1 mL) and NaOH (0.90 g,2.25 mmol).

The reaction is stirred for 3 hours then concentrated under reducedpressure. The remaining oil is acidified to pH —1 with 1M HCl and thesolution is concentrated under reduced pressure to give an off-whitesolid. The solid is suspended in CHCl₃:isopropanol (1:1) then collectedby filtration. The solid is washed with additional CHCl₃:isopropanol(1:1) then transferred to a flask and triturated with Et₂O to afford0.075 g (85% yield) of the desired compound as a pale yellow solid. ¹HNMR (250 MHz, MeOD) δ ppm (rotamers) 8.26 (1H, br s), 7.63-7.74 (1H, m),7.56-7.63 (1H, m), 4.38 (1H, s), 4.32 (1H, s), 3.20 (1.5 H, s), 3.12(1.5 H, s). HPLC-MS: m/z 211 [M+H]⁺.

The following are non-limiting examples of the compounds describedabove.

2-(S)-[(3-Hydroxy-pyridine-2-carbonyl)-amino]-propionic acid methylester: ¹H NMR (250 MHz, CDCl₃) δ ppm 11.86 (1H, s), 8.47 (1H, br s),8.10 (1H, dd, J=4.1, 1.7 Hz), 7.28-7.43 (2H, m), 4.63-4.84 (1H, m), 3.81(3H, s), 1.57 (3H, d, J=7.3 Hz). HPLC-MS: m/z 225 [M+H]⁺.

1-(3-Hydroxy-pyridine-2-carbonyl)-pyrrolidine-2-carboxylic acid methylester: ¹H NMR (250 MHz, CDCl₃) 6 ppm (rotamers) 12.86 (0.67 H, br s),12.44 (0.33 H, br s), 8.14 (0.33 H, t, J=2.9 Hz), 7.98 (0.67 H, dd,J=3.7, 2.1 Hz), 7.24-7.31 (2H, m), 5.38 (0.67 H, dd, J=8.5, 3.4 Hz),4.63-4.75 (0.33 H, m), 4.37 (0.67 H, t, J=6.7 Hz), 3.80-4.01 (1.33 H,m), 3.79 (1H, s), 3.70 (2H, s), 1.87-2.44 (4H, m). HPLC-MS: m/z 251[M+H]⁺.

2S-[(3-Hydroxy-pyridine-2-carbonyl)-amino]-propionic acid: ¹H NMR (250MHz, DMSO-d₆) δ ppm 12.87 (1H, br s), 12.28 (1H, s), 9.19 (1H, d, J=7.5Hz), 8.19 (1H, dd, J=4.3, 1.4 Hz), 7.50-7.65 (1H, m), 7.37-7.49 (1H, m),3.95-4.95 (1H, m), 1.45 (3H, d, J=7.3 Hz). HPLC-MS: m/z 211 [M+H]⁺.

Administration of one or more of the compounds of Formula (I), alone inthe form of pharmaceutical compositions, optionally in combination withother pharmaceutically active compounds or compositions, can beeffective in treatment of the following disease states or conditions:

-   -   i) as human protein HIF-1α prolyl hydroxylase inhibitors; and        thereby providing a means for regulating blood flow, oxygen        delivery and energy utilization in ischemic tissues;    -   ii) the compounds of the present disclosure are efficacious in        regulating blood flow, oxygen delivery and energy utilization in        ischemic tissues; and    -   iii) the compounds of the present disclosure provide stabilized        HIF-1α by blocking a degradation pathway mediated by HIF prolyl        hydroxylase. Each of the disease states or conditions which the        formulator desires to treat may require differing levels or        amounts of the compounds described herein to obtain a        therapeutic level. The formulator can determine this amount by        any of the testing procedures known to the artisan or ordinary        skil in the art.

The compounds of the present disclosure can be HIF-1α prolyl hydroxylaseinhibitors when administered in pharmaceutically effective amounts, andthereby provide increased angiogenic response or cellular responseswhich are activated by transcription factors that are directly orindirectly affected by an increase in cellular HIF-1α concentration.Non-limiting examples of these diseases or disease states are listedherein below, inter alio, Peripheral Vascular Disease (PVD), CoronaryArtery Disease (CAD), heart failure, ischemia, and anemia. The compoundsdisclosed herein are especially effective in the treatment of anemia.

Stimulation of EPO production: anemia

HIF-1 is a transcription factor that also regulates thehypoxia-inducible EPO gene. HIF-1 binding is required for EPOtranscriptional activation in response to hypoxia (Semenza, G.L.,“Regulation of erythropoietin production: New insights into molecularmechanisms of oxygen homeostasis”, Hematol. Oncol. Clin. North Am., Vol.8, pp. 863-884 (1994)). In particular, HIF-1α binds to the 3′hypoxia-response element of the EPO gene which results in the markedenhancement of EPO transcription (Semenza, G. L., et al.“Transcriptional regulation of genes encoding glycolytic enzymes byhypoxia-inducible factor 1”, J. Biol. Chem., Vol. 269, pp. 23757-63(1994)). EPO, in turn, is essential for maintenance of red blood cellsby controlling the proliferation and differentiation of erythroidprogenitor cells into red blood cells (Krantz, S. B., “Erythropoietin,”Blood, Vol. 77, pp 419-434 (1991)). During fetal development, the liverserves as the primary source of EPO. Shortly before birth, production ofEPO in the liver decreases and the kidney becomes the primary source ofEPO. However, in adults other organs such as the liver and brain producesmall but significant amounts of EPO. A erythropoietin deficiency isassociated with anemia. In humans, the most prevalent form of anemia isassociated with kidney failure.

EPO has been described in the treatment of anemia: associated withchemotherapy; that occurs as a consequence of AIDS; and due toprematurity and autologous blood donation. EPO has even been suggestedas a general use agent in pre-operative elective surgery.

Angiogenesis

Angiogenesis, the sprouting of new blood vessels from the pre-existingvasculature, plays a crucial role in a wide range of physiological andpathological processes (Nguyen, L. L. et al., Int. Rev. Cytol., 204,1-48, (2001). Angiogenesis is a complex process, mediated bycommunication between the endothelial cells that line blood vessels andtheir surrounding environment. In the early stages of angiogenesis,tissue or tumor cells produce and secrete pro-angiogenic growth factorsin response to environmental stimuli such as hypoxia. These factorsdiffuse to nearby endothelial cells and stimulate receptors that lead tothe production and secretion of proteases that degrade the surroundingextracellular matrix. The activated endothelial cells begin to migrateand proliferate into the surrounding tissue toward the source of thesegrowth factors (Bussolino, F., Trends Biochem. Sci., 22, 251-256,(1997)). Endothelial cells then stop proliferating and differentiateinto tubular structures, which is the first step in the formation ofstable, mature blood vessels. Subsequently, periendothelial cells, suchas pericytes and smooth muscle cells, are recruited to the newly formedvessel in a further step toward vessel maturation. Angiogenesis isregulated by a balance of naturally occurring pro- and anti-angiogenicfactors. Vascular endothelial growth factor, fibroblast growth factor,and angiopoeitin represent a few of the many potential pro-angiogenicgrowth factors. These ligands bind to their respective receptor tyrosinekinases on the endothelial cell surface and transduce signals thatpromote cell migration and proliferation. Whereas many regulatoryfactors have been identified, the molecular mechanisms of this processare still not fully understood.

There are many disease states driven by persistent unregulated orimproperly regulated angiogenesis. In such disease states, unregulatedor improperly regulated angiogenesis may either cause a particulardisease or exacerbate an existing pathological condition. For example,ocular neovascularization has been implicated as the most common causeof blindness and underlies the pathology of approximately 20 eyediseases. In certain previously existing conditions such as arthritis,newly formed capillary blood vessels invade the joints and destroycartilage. In diabetes, new capillaries formed in the retina invade thevitreous humor, causing bleeding and blindness.

Both the growth and metastasis of solid tumors are alsoangiogenesis-dependent (Folkman et al., “Tumor Angiogenesis,” Chapter10, 206-32, in The Molecular Basis of Cancer, Mendelsohn et al., eds.,W. B. Saunders, (1995)). It has been shown that tumors which enlarge togreater than 2 mm in diameter must obtain their own blood supply and doso by inducing the growth of new capillary blood vessels. After thesenew blood vessels become embedded in the tumor, they provide nutrientsand growth factors essential for tumor growth as well as a means fortumor cells to enter the circulation and metastasize to distant sites,such as liver, lung or bone (Weidner, New Eng. J. Med., 324, 1, 1-8(1991). When used as drugs in tumor-bearing animals, natural inhibitorsof angiogenesis may prevent the growth of small tumors (O'Reilly et al.,Cell, 79, 315-28 (1994). In some protocols, the application of suchinhibitors leads to tumor regression and dormancy even after cessationof treatment (O'Reilly et al., Cell, 88, 277-85 (1997)). Moreover,supplying inhibitors of angiogenesis to certain tumors may potentiatetheir response to other therapeutic regimens (Teischer et al., Int. J.Cancer, 57, 920-25 (1994)).

Peripheral Vascular Disease

Peripheral vascular disease (PVD) is the term used to describe theclinical syndrome of vascular insufficiency outside of the coronarycirculation and typically involving the circulation to the lowerextremities. There are an estimated 8-12 million patients in the US withperipheral vascular disease; another 16.5 million undiagnosed.Atherosclerosis is by far the leading cause of peripheral vasculardisease (PVD), although a number of discrete disease processes cancontribute to its development and progression (i.e. diabetes, immunevasculitis and trauma). Atherosclerotic PVD can present in three ways:

-   -   1) Asymptomatic PVD diagnosed on the basis of noninvasive        testing (usually physical exam);    -   2) Intermittent claudication with symptoms of leg pain with        exercise; and    -   3) Critical limb ischemia with leg pain at rest and        limb-threatening ischemic changes (usually non-healing or        infected cutaneous ulcerations).

The age-adjusted (average age 66 years) prevalence of PVD in the USpopulation is approximately 12%. Of those patients with claudication,20-30% will have progressive symptoms and 10% will require amputationfor critical limb ischemia. Although patients with symptomatic PVDsuffer significant decreases in mobility, muscle mass, bone density andquality of life, there are currently no effective medical therapiesavailable.

The present disclosure provides compounds which when administered invivo inhibit HIF-1α prolyl hydroxylase thereby leading to increasedexpression of HIF-regulated genes, inter alia, angiogenic factors,erythropoietin, and glycolytic enzymes thereby resulting in improvementin blood flow, oxygen delivery and energy utilization in ischemictissues.

Although many disease states are driven by persistent unregulated orimproperly regulated angiogenesis, some disease states could be treatedby increased angiogenesis. Tissue growth and repair are biologic eventswherein cellular proliferation and angiogenesis occur. Thus an importantaspect of wound repair is the revascularization of damaged tissue byangiogenesis.

Wounds

Chronic, non-healing wounds are a major cause of prolonged morbidity inthe aged human population. This is especially the case in bedridden ordiabetic patients who develop severe, non-healing skin ulcers. In manyof these cases, the delay in healing is a result of inadequate bloodsupply either as a result of continuous pressure or of vascularblockage. Poor capillary circulation due to small artery atherosclerosisor venous stasis contributes to the failure to repair damaged tissue.Such tissues are often infected with microorganisms that proliferateunchallenged by the innate defense systems of the body which requirewell vascularized tissue to effectively eliminate pathogenic organisms.As a result, most therapeutic intervention centers on restoring bloodflow to ischemic tissues thereby allowing nutrients and immunologicalfactors access to the site of the wound.

Atherosclerotic Lesions

Atherosclerotic lesions in large vessels may cause tissue ischemia thatcould be ameliorated by modulating blood vessel growth to the affectedtissue. For example, atherosclerotic lesions in the coronary arteriesmay cause angina and myocardial infarction that could be prevented ifone could restore blood flow by stimulating the growth of collateralarteries. Similarly, atherosclerotic lesions in the large arteries thatsupply the legs may cause ischemia in the skeletal muscle that limitsmobility and in some cases necessitates amputation, which may also beprevented by improving blood flow with angiogenic therapy.

Diabetes/Hypertension

Diseases such as diabetes and hypertension are characterized by adecrease in the number and density of small blood vessels such asarterioles and capillaries. These small blood vessels are important forthe delivery of oxygen and nutrients. A decrease in the number anddensity of these vessels contributes to the adverse consequences ofhypertension and diabetes including claudication, ischemic ulcers,accelerated hypertension, and renal failure. These common disorders andmany other less common ailments, such as Burgers disease, could beameliorated by increasing the number and density of small blood vesselsusing angiogenic therapy.

The present disclosure further relates to forms of the presentcompounds, which under normal human or higher mammalian physiologicalconditions, release the compounds described herein. One iteration ofthis aspect includes the pharmaceutically acceptable salts of theanalogs described herein. The formulator, for the purposes ofcompatibility with delivery mode, excipients, and the like, can selectone salt form of the present analogs over another since the compoundsthemselves are the active species which mitigate the disease processesdescribed herein.

Formulations

The present disclosure also relates to compositions or formulationswhich comprise the human protein HIF-1α prolyl hydroxylase inhibitorsaccording to the present disclosure. In general, the compositions of thepresent disclosure comprise:

-   -   a) an effective amount of one or more human protein HIF-1α        prolyl hydroxylase inhibitor according to the present disclosure        which are effective for treating PVD, CAD, heart failure,        ischemia, and anemia; and    -   b) one or more excipients.

For the purposes of the present disclosure the term “excipient” and“carrier” are used interchangeably throughout the description of thepresent disclosure and said terms are defined herein as, “ingredientswhich are used in the practice of formulating a safe and effectivepharmaceutical composition.”

The formulator will understand that excipients are used primarily toserve in delivering a safe, stable, and functional pharmaceutical,serving not only as part of the overall vehicle for delivery but also asa means for achieving effective absorption by the recipient of theactive ingredient. An excipient may fill a role as simple and direct asbeing an inert filler, or an excipient as used herein may be part of apH stabilizing system or coating to insure delivery of the ingredientssafely to the stomach. The formulator can also take advantage of thefact the compounds of the present disclosure have improved cellularpotency, pharmacokinetic properties, as well as improved oralbioavailability.

Non-limiting examples of compositions according to the presentdisclosure include:

-   -   a) from about 0.001 mg to about 1000 mg of one or more human        protein HIF-1α prolyl hydroxylase inhibitor according to the        present disclosure; and    -   b) one or more excipients.

Another example according to the present disclosure relates to thefollowing compositions:

-   -   a) from about 0.01 mg to about 100 mg of one or more human        protein prolyl HIF-1α prolyl hydroxylase inhibitor according to        the present disclosure; and    -   b) one or more excipients.

A further example according to the present disclosure relates to thefollowing compositions:

-   -   a) from about 0.1 mg to about 10 mg of one or more human protein        HIF-1α prolyl hydroxylase inhibitor according to the present        disclosure; and    -   b) one or more excipients.

The term “effective amount” as used herein means “an amount of one ormore HIF-1α prolyl hydroxylase inhibitors, effective at dosages and forperiods of time necessary to achieve the desired or therapeutic result.”An effective amount may vary according to factors known in the art, suchas the disease state, age, sex, and weight of the human or animal beingtreated. Although particular dosage regimes may be described in examplesherein, a person skilled in the art would appreciated that the dosageregime may be altered to provide optimum therapeutic response. Forexample, several divided doses may be administered daily or the dose maybe proportionally reduced as indicated by the exigencies of thetherapeutic situation. In addition, the compositions of the presentdisclosure can be administered as frequently as necessary to achieve atherapeutic amount.

The present disclosure further relates to the use of one or more of theHIF-1α prolyl hydroxylase inhibitors disclosed herein for making amedicament for treating anemia.

The present disclosure further relates to the use of one or more of theHIF-1α prolyl hydroxylase inhibitors disclosed herein for making amedicament for treating angiogenesis.

The present disclosure further relates to the use of one or more of theHIF-1α prolyl hydroxylase inhibitors disclosed herein for making amedicament for treating peripheral vascular disease.

The present disclosure further relates to the use of one or more of theHIF-1α prolyl hydroxylase inhibitors disclosed herein for making amedicament for treating wounds.

The present disclosure further relates to the use of one or more of theHIF-1α prolyl hydroxylase inhibitors disclosed herein for making amedicament for treating atherosclerotic lesions.

The present disclosure further relates to the use of one or more of theHIF-1α prolyl hydroxylase inhibitors disclosed herein for making amedicament for treating diabetes.

The present disclosure further relates to the use of one or more of theHIF-1α prolyl hydroxylase inhibitors disclosed herein for making amedicament for treating hypertension.

The present disclosure further relates to the use of one or more of theHIF-1α prolyl hydroxylase inhibitors disclosed herein for making amedicament for treating a disease affected by the level of VEGF, GAPDHand erythropoietin.

The present disclosure further relates to the use of one or more of theHIF-1α prolyl hydroxylase inhibitors disclosed herein for making amedicament for treating a disorder chosen from Crohn's disease andulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis,hemangiomas, Osler-Weber-Rendu disease, or hereditary hemorrhagictelangiectasia, solid or blood borne tumors and acquired immunedeficiency syndrome.

The present disclosure further relates to the use of one or more of theHIF-1α prolyl hydroxylase inhibitors disclosed herein for making amedicament for treating a disorder chosen from diabetic retinopathy,macular degeneration, cancer, sickle cell anemia, sarcoid, syphilis,pseudoxanthoma elasticum, Paget's disease, vein occlusion, arteryocclusion, carotid obstructive disease, chronic uveitis/vitritis,mycobacterial infections, Lyme's disease, systemic lupus erythematosis,retinopathy of prematurity, Eales' disease, Behcet's disease, infectionscausing a retinitis or choroiditis, presumed ocular histoplasmosis,Best's disease, myopia, optic pits, Stargardt's disease, pars planitis,chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis,trauma and post-laser complications, diseases associated with rubeosis,and proliferative vitreoretinopathy.

Method of Use

By increasing the transcription of these HIF-1 target genes, the HIF-1αprolyl hydroxylase inhibitors of the present disclosure provide a methodfor increasing the vascularization of tissue in a subject. As usedherein, “vascularization of tissue” means a pro-angiogenic responsewhereby blood vessels or other vessels or ducts develop at or around theafflicted tissue. The afflicted tissue need not be hypoxic or ischemicper se, but rather the HIF-1α prolyl hydroxylase inhibitors help tosustain or further stimulate the body's pro-angiogenic response tohypoxia. A non-limiting example of “vascularization” includes capillaryproliferation in a non-healing wound or along the border of ischemictissue. Thus, these compounds enhance the ability of the body torevascularize damaged tissues or increase vasculature (e.g. to preventhypoxic damage). Non-limiting examples of “tissue” include: cardiactissue, such as myocardium and cardiac ventricles; skeletal muscle;neurological tissue, such as from the cerebellum; internal organs, suchas the stomach, intestine, pancreas, liver, spleen, and lung; and distalappendages such as fingers and toes.

Stimulated by a build up of the cellular concentration of HIF-1α is theproduction of Vascular Endothelial Growth Factor (VEGF) which is knownfor its ability to induce vascular leakage. Oxygen tension has beenshown to be a key regulator of VEGF gene expression, both in vitro andin vivo. During VEGF induction it is demonstrated that VEGF induces theformation of functional neo-vessels in the mouse cornea and enhancedblood flow in a dog model of coronary artery disease. The HIF-1α prolylhydroxylase inhibitors of the present disclosure provide enhancement inthe expression of multiple hypoxia inducible genes including VEGF, GAPDHand erythropoietin (EPO). Additionally, the HIF-1α prolyl hydroxylaseinhibitors of the present disclosure provide enhanced the accumulationof HIF1-α in the cytoplasm and nucleus. Transgenic mice expressing aconstitutively active HIF-1α in the skin have increased dermalvascularity and had a 13-fold increase in VEGF levels

The present disclosure also relates to a method for controlling humanprotein HIF1α prolyl hydroxylase. The present method comprises the stepof administering to a human or higher mammal an effective amount of acomposition comprising one or more human protein HIF-1α prolylhydroxylase inhibitors according to the present disclosure.

The present disclosure also relates to the use of the human proteinHIF-1α prolyl hydroxylase inhibitors according to the present disclosurein the manufacture of a medicament for the treatment of atrialarrhythmias and related disorders. The present disclosure also relatesto hypoxia inducible factor HIF-1α prolyl hydroxylase inhibition inmyocardial remodeling and function, thereby providing means for inducingangiogenesis in a patient experiencing ischemia.

The present disclosure relates to a method for treating anemiacomprising administering to a human or mammal in need of treatment aneffective amount of one or more human protein HIF-1α prolyl hydroxylaseinhibitors according to the present disclosure.

The present disclosure relates to a method for regulating anemiacomprising administering to a human or mammal in need of treatment aneffective amount of one or more human protein HIF-1α prolyl hydroxylaseinhibitors according to the present disclosure.

The present disclosure relates to a method for preventing anemiacomprising administering to a human or mammal in need of treatment aneffective amount of one or more human protein HIF-1α prolyl hydroxylaseinhibitors according to the present disclosure.

Procedures EGLN-1 Activity Assay

The EGLN-1 (or EGLN-3) enzyme activity is determined using massspectrometry (matrix-assisted laser desorption ionization,time-of-flight MS, MALDI-TOF MS- for assay details, see reference (Greiset al., 2006). Recombinant human EGLN -1-179/426 is prepared asdescribed above and in the Supplemental Data. Full-length recombinanthuman EGLN-3 is prepared in a similar way, however it is necessary touse the His-MBP-TVMVEGLN-3 fusion for the assay due to the instabilityof the cleaved protein. For both enzymes, the HIF- 1 a peptidecorresponding to residues 556-574 (DLDLEALAPYIPADDDFQL) (SEQ ID NO. 1)is used as substrate. The reaction is conducted in a total volume of 50uL containing TrisCl (5 mM, pH 7.5), ascorbate (120 μM), 2-oxoglutarate(3.2 μM), HIF-1α (8.6 μM), and bovine serum albumin (0.01%). The enzyme,quantity predetermined to hydroxylate 20% of substrate in 20 minutes, isadded to start the reaction. Where inhibitors are used, compounds areprepared in dimethyl sulfoxide at 10-fold final assay concentration.After 20 minutes at room temperature, the reaction is stopped bytransferring 10 μI, of reaction mixture to 50 μI, of a mass spectrometrymatrix solution (a-cyano-4-hydroxycinnamic acid, 5 mg/mL in 50%acetonitrile/0.1% TFA, 5 mM NH₄PO₄). Two microliters of the mixture isspotted onto a MALDI-TOF MS target plate for analysis with an AppliedBiosystems (Foster City, Calif.) 4700 Proteomics Analyzer MALDI-TOF MSequipped with a Nd:YAG laser (355 nm, 3 ns pulse width, 200 Hzrepetition rate). Hydroxylated peptide product is identified fromsubstrate by the gain of 16 Da. Data defined as percent conversion ofsubstrate to product is analyzed in GraphPad Prism 4 to calculate IC₅₀values.

VEGF ELISA Assay

HEK293 cells are seeded in 96-well poly-lysine coated plates at 20,000cells per well in DMEM (10% FBS, 1% NEAA, 0.1% glutamine). Followingovernight incubation, the cells are washed with 100 uL of Opti-MEM(Gibco, Carlsbad, Calif.) to remove serum. Compound in DMSO is seriallydiluted (beginning with 100 μM) in Opti-MEM and added to the cells. Theconditioned media is analyzed for VEGF with a Quantikine human VEGFimmunoassay kit (R&D Systems, Minneapolis, Minn.). Optical densitymeasurements at 450nm are recorded using the Spectra Max 250 (MolecularDevices, Sunnyvale, Calif.). Data defined as % of DFO stimulation isused to calculate EC₅₀ values with GraphPad Prism 4 software (San Diego,Calif.).

Mouse Ischemic Hindlimb Study

All animal work is conducted in accordance with the Guide for the Careand Use of Laboratory Animals (National Academy of Sciences; Copyright01996) and the Institutional Animal Care and Use Committee guidelines atProcter and Gamble Pharmaceuticals. We studied 9-10 week old maleC57B1/6 mice from Charles River Laboratory (Portage, Mich.). The miceare orally dosed with vehicle (aqueous carbonate buffer, 50 mM; pH 9.0)or compound 1 in vehicle at 50 mg/kg or 100 mg/kg. The animals are dosedthree times: day 1 at 8 am and 5 pm, day 2 at 8 am. One hour after thefirst dose, unilateral arterial ligation is performed under anesthesiausing isoflurane. The femoral artery is ligated proximal to the originof the popliteal artery. The contralateral limb underwent a shamsurgical procedure. Ligation is performed in an alternating fashionbetween right and left hindlimbs. Two hours after Sam dosing on day 2,we obtained blood by ventricular stick while the mice are anesthetizedwith isoflurane. Serum samples for EPO analysis are obtained using gelclot serum separation tubes. Heart, liver, and gastrocnemius muscles areharvested, snap-frozen in liquid nitrogen, and stored in −80° C. untiluse.

Mouse Serum EPO Assay

The mouse serum EPO is detected using Mouse Quantikine ErythropoietinELISA kit from R&D Systems according to manufacturer's instructions.

Mouse Tissue HIF Western Blot Analysis

Tissues from mice stored at -80° C. are powdered with mortar and pestlechilled with liquid nitrogen. Nuclear extracts are prepared using anNE-PER kit (Pierce Biotechnology). For immunoprecipitation, nuclearextract is added to monoclonal antibody to HIF-1α (Novus, Littleton,Colo.) at a tissue to antibody ratio of 200:1. The suspension isincubated in a conical micro centrifuge tube for 4 hours at 4° C.Protein A/G-coupled agarose beads (40 ul of a 50% suspension) are thenadded to the tube. Following overnight tumbling at 4° C., the beads arewashed 3 times with ice-cold phosphate buffered saline. The beads arethen prepared for SDS-PAGE with 40 ul of Laemmli sample buffer. Proteinsseparated on SDS-PAGE are transferred onto nitrocellulose sheets withXCell-II Blot Module system (Invitrogen, Carlsbad, Calif.). The blotsare blocked with 5% BSA prior to incubation with a rabbit antibody toHIF-1α at 1:100 dilution (Novus). The blots are then washed withTris-buffered saline/Tween-20 buffer and incubated with horseradishperoxidase-conjugated goat anti-rabbit secondary antibody (Pierce,Rockford, Ill.). Blots are developed with the ECL reagent (Amersham,Piscataway, N.J.). Images of blots are captured with an Epson Expression1600 scanner.

Table XV below provides non-limiting examples of the in vivo responsefor compounds according to the present disclosure.

TABLE XV VEGF EGLIN1 EGLIN3 EC₅₀ EPO Compound IC₅₀ μM IC₅₀ μM μMresponse

2.8 21.4 9.9 (39) yes

3.7 — >100  ND*

5.8 — >100 ND

0.65 0.18 42.1 yes

20 — >100 yes

4.1 52.3 8.2 ND

6.8 37.5 7.7 yes

0099 0.56 4.3 yes

0.24 0.083 — yes

0.41 — 7.6 ND

1.1 0.39 — yes

1.1 0.39 — yes

0.44 — 15 —

0.3 — >100 —

1.6 — >100 —

2.5 — 3.3 —

1.2 1.3 1.4 yes

5.1 — >100 ND

2.6 — >100 ND

0.19 — >100 ND

11.2 — 50.1 ND

2.5 — >100 ND

0.3 — >100 ND

0.4 — >100 ND

9.2 — — ND *ND = not determined.

While particular embodiments of the present disclosure have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the disclosure. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this disclosure.

1.-32. (canceled)
 33. A process for preparing a compound having theformula:

comprising: (a) reacting a 4-chlorophenyl boronic acid:

with methyl 4-bromo-2-methoxybenzoate:

in the presence of a catalyst to form4′-chloro-3-methoxy-biphenyl-4-carboxylic acid methyl ester:

(b) reacting 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid methyl esterobtained from step (a) with lithium hydroxide to form4′-chloro-3-methoxy-biphenyl carboxylic acid:

and (c) reacting 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid obtainedfrom step (b) with glycine ethyl ester, in the presence of couplingagents to form [(4′-chloro-3-methoxy-biphenyl-4-carbonyl)-amino]-aceticacid ethyl ester:


34. The process of claim 33, further comprising reacting[(4′-chloro-3-methoxy-biphenyl-4-carbonyl)-amino]-acetic acid ethylester:

with BBr₃ to form[(4′-Chloro-3-hydroxy-biphenyl-4-carbonyl)-amino]-acetic acid:


35. The process of claim 33, wherein the catalyst in step (a) is[1,1′-bis (diphenylphosphino)ferrocine]dichloro palladium(II).
 36. Theprocess of claim 33, wherein the reaction in step (a) is conducted inthe presence of a base that is K₃PO₄.
 37. The process of claim 33,wherein the coupling reagents in step (c) are1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCl) and1-hydroxybenzotriazole (HOBt).
 38. A pharmaceutical compositioncomprising (1) a pharmaceutically acceptable excipient, and (2) acompound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R is2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-cyanophenyl, 3-cyanophenyl,4-cyanophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl,4-ethoxyphenyl, 2-iso-propoxyphenyl, 3-iso-propoxyphenyl,4-iso-propoxyphenyl, 2-carbamoylphenyl, 3-carbamoylphenyl,4-carbamoylphenyl, 2-(aziridine-1-carbonyl)phenyl,3-(aziridine-1-carbonyl)phenyl, 4-(aziridine-1-carbonyl)phenyl,2-(azetidine-1-carbonyl)phenyl, 3-(azetidine-1-carbonyl)phenyl,4-(azetidine-1-carbonyl)phenyl, 2-(pyrrolidine-1-carbonyl)phenyl,3-(pyrrolidine-1-carbonyl)phenyl, 4-(pyrrolidine-1-carbonyl)phenyl,2-(piperidine-1-carbonyl)phenyl, 3-(piperidine-1-carbonyl)phenyl,4-(piperidine-1-carbonyl)phenyl, 2-(acetylamino)phenyl,3-(acetylamino)phenyl, 4-(acetylamino)phenyl,2-(ethanecarbonylamino)phenyl, 3-(ethanecarbonylamino)phenyl,4-(ethanecarbonylamino)phenyl, 2-(cyclopropanecarbonylamino)phenyl,3-(cyclopropanecarbonylamino)phenyl, or4-(cyclopropanecarbonylamino)phenyl.
 39. The pharmaceutical compositionof claim 38, comprising

or a pharmaceutically acceptable salt thereof.